bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–10–13
71 papers selected by
Viktor Korolchuk, Newcastle University
  1. Apache is a neuronal player in autophagy required for retrograde axonal transport of autophagosomes.
  2. Biogenesis of omegasomes and autophagosomes in mammalian autophagy.
  3. Spatial and functional separation of mTORC1 signalling in response to different amino acid sources.
  4. Coordinating BNIP3/NIX-mediated mitophagy in space and time.
  5. Phospholipase D3 regulates TFEB/TFE3 metabolism to maintain lysosomal homeostasis.
  6. CRISPR activation of Tfeb , a master regulator of autophagy and lysosomal biogenesis, in osteoblast lineage cells increases bone mass and strength.
  7. Autophagy and the pancreas: Healthy and disease states.
  8. SIGMAR1/Sigma-1 receptor: a key regulator in stabilizing and translating LC3B mRNA for autophagosome formation.
  9. AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
  10. Navigating therapeutic prospects by modulating autophagy in colorectal cancer.
  11. Discovery of sp3-rich diazatricycloundecanes as lysosomotropic autophagy inhibitors.
  12. Drug repositioning identifies potential autophagy inhibitors for the LIR motif p62/SQSTM1 protein.
  13. Siah3 acts as a physiological mitophagy suppressor that facilitates axonal degeneration.
  14. The p97-UBXD8 complex maintains peroxisome abundance by suppressing pexophagy.
  15. O-GlcNAcylation modulates mTORC1 and autophagy in β-cells, driving diabetes progression.
  16. Bulk and selective autophagy cooperate to remodel a fungal proteome in response to changing nutrient availability.
  17. SCYL1-mediated regulation of the mTORC1 signaling pathway inhibits autophagy and promotes gastric cancer metastasis.
  18. Atrial natriuretic peptide (ANP) modulates stress-induced autophagy in endothelial cells.
  19. Hyperactive mTORC1/4EBP1 signaling dysregulates proteostasis and accelerates cardiac aging.
  20. A Siah3 of relief: A role for mitophagy as a fail-safe during developmental axon pruning.
  21. Advances in natural products modulating autophagy influenced by cellular stress conditions and their anticancer roles in the treatment of ovarian cancer.
  22. Transcription factor EB (TFEB) promotes autophagy in early brain injury after subarachnoid hemorrhage in rats.
  23. DNA Nanotechnology for Application in Targeted Protein Degradation.
  24. In vitro and in vivo reconstitution systems reveal the membrane remodeling ability of LC3B and ATG16L1 to form phagophore-like membrane cups.
  25. Chaperone-mediated autophagy modulates Snail protein stability: implications for breast cancer metastasis.
  26. Autophagy as a targeted therapeutic approach for skin cancer: Evaluating natural and synthetic molecular interventions.
  27. DDX3X dynamics, glioblastoma's genetic landscape, therapeutic advances, and autophagic interplay.
  28. KIF1C facilitates retrograde transport of lysosomes through Hook3 and dynein.
  29. The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
  30. miRNA375-3p/rapamycin mediates the mTOR pathway by decreasing PS1, enhances microglial cell activity to regulate autophagy in Alzheimer's disease.
  31. Regulatory Mechanisms Governing the Autophagy-Initiating VPS34 Complex and Its inhibitors.
  32. CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction.
  33. Proteomic characterization of ubiquitin carboxyl-terminal hydrolase 19 deficient cells reveals a role for USP19 in secretion of lysosomal proteins.
  34. Lysosomal LRRC8 complex regulates lysosomal pH, morphology and systemic glucose metabolism.
  35. Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats.
  36. Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.
  37. Bridge-like lipid transfer protein 3A (BLTP3A) is associated with membranes of the late endocytic pathway and is an effector of CASM.
  38. The lysosomal lipid transporter LIMP-2/SCARB2 is part of lysosome-endoplasmic reticulum STARD3-VAPB-dependent contact sites.
  39. Elucidating the power of arginine restriction: taming type I interferon response in breast cancer via selective autophagy.
  40. SARS-CoV-2 ORF3a Protein Impairs Syncytiotrophoblast Maturation, Alters ZO-1 Localization, and Shifts Autophagic Pathways in Trophoblast Cells and 3D Organoids.
  41. A novel strategy to enhance inhibition of Hela cervical cancer by combining Lentinus β-glucan and autophagic flux blockage.
  42. Molecular basis of the recognition of the active Rab8a by Optineurin.
  43. Autophagy controls neuronal differentiation by regulating the WNT-DVL signaling pathway.
  44. Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool.
  45. Crosstalk between mitochondria-ER contact sites and the apoptotic machinery as a novel health meter.
  46. LINC00941 is a diagnostic biomarker for lung adenocarcinoma and promotes tumorigenesis through cell autophagy.
  47. The role of TFEB-mediated autophagy-lysosome dysfunction in manganese neurotoxicity.
  48. Modeling Parkinson's disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines.
  49. GDF15 enhances anoikis resistance and metastasis of gastric cancer through protective autophagy.
  50. Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance.
  51. TMEM164 promotes ferroptosis by selectively mediating ATG5-dependent autophagosome formation to inhibit the progression of LUAD.
  52. Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway.
  53. miR-7 promotes apoptosis and autophagy of granulosa cells by targeting KLF4 via JAK/STAT3 signaling pathway in chickens.
  54. Endo-IP and Lyso-IP Toolkit for Endolysosomal Profiling of Human Induced Neurons.
  55. Sonocatalysis Regulates Tumor Autophagy for Enhanced Immunotherapy.
  56. Regulation of autophagy by non-coding RNAs in human glioblastoma.
  57. Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease.
  58. Differential roles of N- and C-terminal LIR motifs in the catalytic activity and membrane targeting of RavZ and ATG4B proteins.
  59. Dietary glutamine supplementation improves both Th1 and Th17 responses via CARD11-mTORC1 pathway in murine model of atopic dermatitis.
  60. Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules.
  61. Mechanism of phospho-Ubls' specificity and conformational changes that regulate Parkin activity.
  62. Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo.
  63. Acyl CoA binding protein (ACBP): an autophagy checkpoint that can be targeted for improving cancer immunosurveillance.
  64. Cytoplasmic mtDNA clearance suppresses inflammatory immune responses.
  65. 5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage.
  66. Tumor-associated macrophages/C-X-C motif chemokine ligand 1 promotes breast cancer autophagy-mediated chemoresistance via IGF1R/STAT3/HMGB1 signaling.
  67. Interplay of α-Synuclein Oligomers and Endoplasmic Reticulum Stress in Parkinson'S Disease: Insights into Cellular Dysfunctions.
  68. Glycolysis-mTORC1 crosstalk drives proliferation of patient-derived endometrial cancer spheroid cells with ALDH activity.
  69. TMEM132A regulates Wnt/β-catenin signaling through stabilizing LRP6 during mouse embryonic development.
  70. Nanomaterial-mediated host directed therapy of tuberculosis by manipulating macrophage autophagy.
  71. Apoptosis, autophagy, ferroptosis, and pyroptosis in cisplatin-induced ototoxicity and protective agents.
  1. Cell Mol Life Sci. 2024 Oct 05. 81(1): 416
    Apache is a neuronal player in autophagy required for retrograde axonal transport of autophagosomes.
    Barbara Parisi, Alessandro Esposito, Enrico Castroflorio, Mattia Bramini, Sara Pepe, Antonella Marte, Fabrizia C Guarnieri, Flavia Valtorta, Pietro Baldelli, Fabio Benfenati, Anna Fassio, Silvia Giovedì.
      Neurons are dependent on efficient quality control mechanisms to maintain cellular homeostasis and function due to their polarization and long-life span. Autophagy is a lysosomal degradative pathway that provides nutrients during starvation and recycles damaged and/or aged proteins and organelles. In neurons, autophagosomes constitutively form in distal axons and at synapses and are trafficked retrogradely to the cell soma to fuse with lysosomes for cargo degradation. How the neuronal autophagy pathway is organized and controlled remains poorly understood. Several presynaptic endocytic proteins have been shown to regulate both synaptic vesicle recycling and autophagy. Here, by combining electron, fluorescence, and live imaging microscopy with biochemical analysis, we show that the neuron-specific protein APache, a presynaptic AP-2 interactor, functions in neurons as an important player in the autophagy process, regulating the retrograde transport of autophagosomes. We found that APache colocalizes and co-traffics with autophagosomes in primary cortical neurons and that induction of autophagy by mTOR inhibition increases LC3 and APache protein levels at synaptic boutons. APache silencing causes a blockade of autophagic flux preventing the clearance of p62/SQSTM1, leading to a severe accumulation of autophagosomes and amphisomes at synaptic terminals and along neurites due to defective retrograde transport of TrkB-containing signaling amphisomes along the axons. Together, our data identify APache as a regulator of the autophagic cycle, potentially in cooperation with AP-2, and hypothesize that its dysfunctions contribute to the early synaptic impairments in neurodegenerative conditions associated with impaired autophagy.
    Keywords:  AP-2; Amphisome; LC3; Retrograde trafficking; Synapse; Torin1; TrkB; mTOR
    DOI:  https://doi.org/10.1007/s00018-024-05441-7
  2. Biochem Soc Trans. 2024 Oct 11. pii: BST20240015. [Epub ahead of print]
    Biogenesis of omegasomes and autophagosomes in mammalian autophagy.
    Puck N Norell, Daniele Campisi, Jagan Mohan, Thomas Wollert.
      Autophagy is a highly conserved catabolic pathway that maintains cellular homeostasis by promoting the degradation of damaged or superfluous cytoplasmic material. A hallmark of autophagy is the generation of membrane cisternae that sequester autophagic cargo. Expansion of these structures allows cargo to be engulfed in a highly selective and exclusive manner. Cytotoxic stress or starvation induces the formation of autophagosomes that sequester bulk cytoplasm instead of selected cargo. This rather nonselective pathway is essential for maintaining vital cellular functions during adverse conditions and is thus a major stress response pathway. Both selective and nonselective autophagy rely on the same molecular machinery. However, due to the different nature of cargo to be sequestered, the involved molecular mechanisms are fundamentally different. Although intense research over the past decades has advanced our understanding of autophagy, fundamental questions remain to be addressed. This review will focus on molecular principles and open questions regarding the formation of omegasomes and phagophores in nonselective mammalian autophagy.
    Keywords:  autophagy; nonselective autophagy; omegasome; phagophore
    DOI:  https://doi.org/10.1042/BST20240015
  3. Nat Cell Biol. 2024 Oct 09.
    Spatial and functional separation of mTORC1 signalling in response to different amino acid sources.
    Stephanie A Fernandes, Danai-Dimitra Angelidaki, Julian Nüchel, Jiyoung Pan, Peter Gollwitzer, Yoav Elkis, Filippo Artoni, Sabine Wilhelm, Marija Kovacevic-Sarmiento, Constantinos Demetriades.
      Amino acid (AA) availability is a robust determinant of cell growth through controlling mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. According to the predominant model in the field, AA sufficiency drives the recruitment and activation of mTORC1 on the lysosomal surface by the heterodimeric Rag GTPases, from where it coordinates the majority of cellular processes. Importantly, however, the teleonomy of the proposed lysosomal regulation of mTORC1 and where mTORC1 acts on its effector proteins remain enigmatic. Here, by using multiple pharmacological and genetic means to perturb the lysosomal AA-sensing and protein recycling machineries, we describe the spatial separation of mTORC1 regulation and downstream functions in mammalian cells, with lysosomal and non-lysosomal mTORC1 phosphorylating distinct substrates in response to different AA sources. Moreover, we reveal that a fraction of mTOR localizes at lysosomes owing to basal lysosomal proteolysis that locally supplies new AAs, even in cells grown in the presence of extracellular nutrients, whereas cytoplasmic mTORC1 is regulated by exogenous AAs. Overall, our study substantially expands our knowledge about the topology of mTORC1 regulation by AAs and hints at the existence of distinct, Rag- and lysosome-independent mechanisms that control its activity at other subcellular locations. Given the importance of mTORC1 signalling and AA sensing for human ageing and disease, our findings will probably pave the way towards the identification of function-specific mTORC1 regulators and thus highlight more effective targets for drug discovery against conditions with dysregulated mTORC1 activity in the future.
    DOI:  https://doi.org/10.1038/s41556-024-01523-7
  4. Biochem Soc Trans. 2024 Oct 08. pii: BST20221364. [Epub ahead of print]
    Coordinating BNIP3/NIX-mediated mitophagy in space and time.
    Natalie M Niemi, Jonathan R Friedman.
      Mitochondria maintain organellar homeostasis through multiple quality control pathways, including the clearance of defective or unwanted mitochondria by selective autophagy. This removal of mitochondria, mitophagy, is controlled in large part by the outer mitochondrial membrane mitophagy receptors BNIP3 and NIX. While it has long been appreciated that BNIP3 and NIX mediate mitophagy by controlling the recruitment of autophagic machinery to the mitochondrial surface, the requirement for the carefully controlled spatiotemporal regulation of receptor-mediated mitophagy has only recently come to light. Several new factors that regulate the BNIP3/NIX-mediated mitophagy pathway have emerged, and various loss-of-function cell and animal models have revealed the dire consequences of their dysregulation. In this mini-review, we discuss new insights into the mechanisms and roles of the regulation of BNIP3 and NIX and highlight questions that have emerged from the identification of these new regulators.
    Keywords:  autophagy; mitochondria; mitophagy
    DOI:  https://doi.org/10.1042/BST20221364
  5. bioRxiv. 2024 Sep 26. pii: 2024.09.26.615214. [Epub ahead of print]
    Phospholipase D3 regulates TFEB/TFE3 metabolism to maintain lysosomal homeostasis.
    Yongchao Wang, Paige Rieschick, Wilber Romero-Fernandez, Nathan Appelbaum, Cristian Carvajal-Tapia, Alena Shostak, Matthew Schrag.
      A coding variant in Phospholipase D3 ( PLD3 ) increases the risk of Alzheimer's disease (AD). PLD3 is a lysosomal protein, and endosomal and lysosomal abnormalities are linked to AD; however, the role of PLD3 in lysosomal homeostasis and its implications in AD remain poorly understood. To address this knowledge gap, we conducted comprehensive studies integrating transcriptomics, proteomics, and cell biology approaches. We observed significant enlargement of lysosomes in neurons lacking PLD3, accompanied by increased endocytosis and autophagy, but a decline in lysosomal proteolytic activity. Lysosomes of PLD3-deficient cells underwent proteome remodeling, manifested by an enrichment of proteins involved in lysosomal biogenesis, endocytosis and calcium signaling. Mechanistically, we discovered that PLD3 mediates TFEB/TFE3 degradation through the proteasome, and as a result, PLD3 deficiency leads to increased TFEB/TFE3 levels, nuclear translocation, and transcriptional activities. Notably, variants in PLD3, e.g., V232M or K486R, do not alter its impact on TFEB/TFE3 metabolism. Transcriptomic profiling further confirmed the enrichment of transcripts involved in lysosomal biogenesis, endocytosis, autophagy, mTOR signaling and AD in response to PLD3 loss. Additionally, PLD3 ablation has synergistic effects with β-amyloid in causing lysosomal abnormalities and modifying TFEB/TFE3 signaling. In conclusion, our findings demonstrate that PLD3 is involved in regulating lysosomal biogenesis via TFEB/TFE3 signaling, and lysosomal abnormalities resulting from PLD3 deficiency are potentially a risk factor for AD.
    DOI:  https://doi.org/10.1101/2024.09.26.615214
  6. bioRxiv. 2024 Sep 26. pii: 2024.09.26.615175. [Epub ahead of print]
    CRISPR activation of Tfeb , a master regulator of autophagy and lysosomal biogenesis, in osteoblast lineage cells increases bone mass and strength.
    Alicen James, James Hendrixson, Ilham Kadhim, Adriana Marques-Carvalho, Jacob Laster, Julie Crawford, Jeff Thostenson, Amy Sato, Maria Almeida, Melda Onal.
      Autophagy is a recycling pathway in which damaged or dysfunctional proteins, protein aggregates, and organelles are delivered to lysosomes for degradation. Insufficiency of autophagy is thought to contribute to several age-related diseases including osteoporosis. Consistent with this, elimination of autophagy from the osteoblast lineage reduces bone formation and causes low bone mass. However, whether increasing autophagy would benefit bone health is unknown. Here, we increased expression of the endogenous Transcription Factor EB gene ( Tfeb ) in osteoblast lineage cells in vivo via CRISPR activation. Tfeb overexpression stimulated autophagy and lysosomal biogenesis in osteoblasts. Tfeb overexpressing male mice displayed a robust increase in femoral and vertebral cortical thickness at 4.5 months of age. Histomorphometric analysis revealed that the increase in femoral cortical thickness was due to increased bone formation at the periosteal surface. Tfeb overexpression also increased femoral trabecular bone volume. Consistent with these results, bone strength was increased in Tfeb overexpressing mice. Female Tfeb overexpressing mice also displayed a progressive increase in bone mass over time and at 12 months of age had high cortical thickness and trabecular bone volume. This increase in vertebral trabecular bone volume was due to elevated bone formation. Osteoblastic cultures showed that Tfeb overexpression increased proliferation and osteoblast formation. Overall, these results demonstrate that stimulation of autophagy in osteoblast lineage cells promotes bone formation and strength and may represent an effective approach to combat osteoporosis.
    DOI:  https://doi.org/10.1101/2024.09.26.615175
  7. Front Cell Dev Biol. 2024 ;12 1460616
    Autophagy and the pancreas: Healthy and disease states.
    Zixian Zhou, Pengcheng Zhang, Juan Li, Jiaqi Yao, Yuhong Jiang, Meihua Wan, Wenfu Tang, Ling Liu.
      Macroautophagy/autophagy is an intracellular degradation pathway that has an important effect on both healthy and diseased pancreases. It protects the structure and function of the pancreas by maintaining organelle homeostasis and removing damaged organelles. A variety of pancreas-related diseases, such as diabetes, pancreatitis, and pancreatic cancer, are closely associated with autophagy. Genetic studies that address autophagy confirm this view. Loss of autophagy homeostasis (lack or overactivation) can lead to a series of adverse reactions, such as oxidative accumulation, increased inflammation, and cell death. There is growing evidence that stimulating or inhibiting autophagy is a potential therapeutic strategy for various pancreatic diseases. In this review, we discuss the multiple roles of autophagy in physiological and pathological conditions of the pancreas, including its role as a protective or pathogenic factor.
    Keywords:  autophagy; genetic studies; organelle homeostasis; pancreas; zymophagy
    DOI:  https://doi.org/10.3389/fcell.2024.1460616
  8. Autophagy. 2024 Oct 10. 1-3
    SIGMAR1/Sigma-1 receptor: a key regulator in stabilizing and translating LC3B mRNA for autophagosome formation.
    Yu-Jie Chen, Jeffrey Knupp, Emily Wang, Peter Arvan, Billy Tsai.
      Macroautophagy/autophagy degrades and recycles cellular constituents via the lysosome to maintain cellular homeostasis. Our study identified the endoplasmic reticulum (ER)-resident SIGMAR1 (sigma non-opioid intracellular receptor 1) as a critical regulator of the biosynthesis of Atg8-family proteins that leads to the lipidation that is essential during autophagosome formation. We demonstrate that SIGMAR1 stabilizes MAP1LC3B/LC3B and GABARAP mRNAs, promoting their localized translation proximal to the ER for efficient lipidation. Using single-molecule fluorescence in situ hybridization/smFISH and co-immunoprecipitation, we found that SIGMAR1 directly binds to a conserved region in the 3' UTR of LC3B mRNA, facilitating its translation, efficient lipidation, and proper integration into the phagophore membrane. Cells lacking SIGMAR1 show reduced levels of many Atg8-family proteins and impaired autophagic flux. Our model suggests that SIGMAR1-mediated localized translation of Atg8-family proteins at the ER promotes efficient autophagosome formation, in contrast to recruiting preexisting cytosolic Atg8-family proteins to the lipidation machinery. Elucidating the role of SIGMAR1 in autophagy may provide better therapeutic strategies to prevent or treat autophagy-dependent neurodegenerative diseases, particularly given the highly druggable nature of SIGMAR1.
    Keywords:  ATG8; LC3; SIGMAR1; autophagy; lipidation; localized translation
    DOI:  https://doi.org/10.1080/15548627.2024.2413313
  9. bioRxiv. 2024 Sep 23. pii: 2024.09.23.614519. [Epub ahead of print]
    AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
    Yann Cormerais, Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Jong Shin, Benjamin Stefadu, Jean Personnaz, Sandra Schrotter, Angelica D'Amore, Emma R Martin, Catherine L Salussolia, Mustafa Sahin, Suchithra Menon, Vanessa Byles, Brendan D Manning.
      Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse intracellular and extracellular growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling established through biochemical and cell biological studies function under physiological states in specific mammalian tissues are unknown. Here, we characterize a genetic mouse model lacking the 5 phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can active mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as brain and skeletal muscle, associated with cell intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mouse model demonstrates that TSC2 phosphorylation is a primary mechanism of mTORC1 activation in some, but not all, tissues and provides a genetic tool to facilitate studies on the physiological regulation of mTORC1.
    DOI:  https://doi.org/10.1101/2024.09.23.614519
  10. Life Sci. 2024 Oct 08. pii: S0024-3205(24)00711-2. [Epub ahead of print] 123121
    Navigating therapeutic prospects by modulating autophagy in colorectal cancer.
    Deepa Rajendran, Chern Ein Oon.
      Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.
    Keywords:  Autophagy; Cell death; Chemoresistance; Colorectal cancer
    DOI:  https://doi.org/10.1016/j.lfs.2024.123121
  11. Eur J Med Chem. 2024 Oct 05. pii: S0223-5234(24)00804-3. [Epub ahead of print]280 116923
    Discovery of sp3-rich diazatricycloundecanes as lysosomotropic autophagy inhibitors.
    Kazuki Miura, Tomoya Doi, Kohei Umedera, Hiroyuki Nakamura.
      We have discovered lysosomotropic autophagy inhibitors from our compound library of sp3-rich diazatricycloundecane skeletons. Compound 1u was identified as the most potent biological activity for LC3-II protein accumulation through the structure-activity relationships (SARs) for LC3-II protein accumulation and anti-proliferative activity at the three freely available substituents (R1-R3) in the diazatricycloundecane skeleton. Compound 1u inhibited lysosome-dependent degradation without affecting autophagosome formation. Furthermore, compound 1u enlarged lysosomes and raised lysosomal pH similar to lysosomotropic agents such as chloroquine, resulting in inhibiting late-stage autophagy by inducing lysosomal dysfunction. Moreover, compound 1u exhibits excellent drug-like chemical properties, not previously reported for lysosomotropic agents.
    Keywords:  Autophagy; Lysosomotropic agent; Structure-activity relationship; Three-dimensional skeleton; sp(3)-rich
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116923
  12. Comput Biol Chem. 2024 Oct 03. pii: S1476-9271(24)00223-8. [Epub ahead of print]113 108235
    Drug repositioning identifies potential autophagy inhibitors for the LIR motif p62/SQSTM1 protein.
    Narjes Asghari, Ali Kian Saei, Marco Cordani, Zahra Nayeri, Mohammad Amin Moosavi.
      Autophagy is a critical cellular process for degrading damaged organelles and proteins under stressful conditions and has casually been shown to contribute to tumor survival and drug resistance. Sequestosome-1 (SQSTM1/p62) is an autophagy receptor that interacts with its binding partners via the LC3-interacting region (LIR). The p62 protein has been a highly researched target for its critical role in selective autophagy. In this study, we aimed to identify FDA-approved drugs that bind to the LIR motif of p62 and inhibit its LIR function, which could be useful targets for modulating autophagy. To this, the homology model of the p62 protein was predicted using biological data, and docking analysis was performed using Molegro Virtual Docker and PyRx softwares. We further assessed the toxicity profile of the drugs using the ProTox-II server and performed dynamics simulations on the effective candidate drugs identified. The results revealed that the kanamycin, velpatasvir, verteporfin, and temoporfin significantly decreased the binding of LIR to the p62 protein. Finally, we experimentally confirmed that Kanamycin can inhibit autophagy-associated acidic vesicular formation in breast cancer MCF-7 and MDA-MB 231 cells. These repositioned drugs may represent novel autophagy modulators in clinical management, warranting further investigation.
    Keywords:  Autophagy; Drug repurposing; LIR motif; Molecular dynamic; P62/SQSTM1; Virtual screening
    DOI:  https://doi.org/10.1016/j.compbiolchem.2024.108235
  13. Sci Signal. 2024 10 08. 17(857): eadn5805
    Siah3 acts as a physiological mitophagy suppressor that facilitates axonal degeneration.
    Omer Abraham, Shifra Ben-Dor, Inna Goliand, Rebecca Haffner-Krausz, Sarah Phoebeluc Colaiuta, Andrew Kovalenko, Avraham Yaron.
      Mitophagy eliminates dysfunctional mitochondria, and defects in this cellular housekeeping mechanism are implicated in various age-related diseases. Here, we found that mitophagy suppression by the protein Siah3 promoted developmental axonal remodeling in mice. Siah3-deficient mice displayed increased peripheral sensory innervation. Cultured Siah3-deficient sensory neurons exhibited delays in both axonal degeneration and caspase-3 activation in response to withdrawal of nerve growth factor. Mechanistically, Siah3 was transcriptionally induced by the loss of trophic support and formed a complex with the cytosolic E3 ubiquitin ligase parkin, a core component of mitophagy, in transfected cells. Axons of Siah3-deficient neurons mounted profound mitophagy upon initiation of degeneration but not under basal conditions. Neurons lacking both Siah3 and parkin did not exhibit the delay in trophic deprivation-induced axonal degeneration or the induction of axonal mitophagy that was seen in Siah3-deficient neurons. Our findings reveal that mitophagy regulation acts as a gatekeeper of a physiological axon elimination program.
    DOI:  https://doi.org/10.1126/scisignal.adn5805
  14. bioRxiv. 2024 Sep 26. pii: 2024.09.24.614749. [Epub ahead of print]
    The p97-UBXD8 complex maintains peroxisome abundance by suppressing pexophagy.
    Iris D Montes, Suganthan Amirthagunanathan, Amit S Joshi, Malavika Raman.
      Peroxisomes are vital organelles involved in key metabolic functions in eukaryotic cells. Their significance is highlighted by peroxisome biogenesis disorders; severe childhood diseases marked by disrupted lipid metabolism. One mechanism regulating peroxisome abundance is through selective ubiquitylation of peroxisomal membrane proteins that triggers peroxisome degradation via selective autophagy (pexophagy). However, the mechanisms regulating pexophagy remain poorly understood in mammalian cells. Here we show that the evolutionarily conserved AAA-ATPase p97 and its membrane embedded adaptor UBXD8 are essential for maintaining peroxisome abundance. From quantitative proteomic studies we reveal that loss of UBXD8 affects many peroxisomal proteins. We find depletion of UBXD8 results in a loss of peroxisomes in a manner that is independent of the known role of UBXD8 in ER associated degradation (ERAD). Loss of UBXD8 or inhibition of p97 increases peroxisomal turnover through autophagy and can be rescued by depleting key autophagy proteins or overexpressing the deubiquitylating enzyme USP30. Furthermore, we find increased ubiquitylation of the peroxisomal membrane protein PMP70 in cells lacking UBXD8 or p97. Collectively, our findings identify a new role for the p97-UBXD8 complex in regulating peroxisome abundance by suppressing pexophagy.
    DOI:  https://doi.org/10.1101/2024.09.24.614749
  15. JCI Insight. 2024 Oct 10. pii: e183033. [Epub ahead of print]
    O-GlcNAcylation modulates mTORC1 and autophagy in β-cells, driving diabetes progression.
    Seokwon Jo, Nicholas Esch, Anh Nguyen, Alicia Wong, Ramkumar Mohan, Clara Kim, Manuel Blandino-Rosano, Ernesto Bernal-Mizrachi, Emilyn U Alejandro.
      Type 2 diabetes (T2D) arises when pancreatic β-cells fail to produce sufficient insulin to control blood glucose appropriately. Aberrant nutrient sensing by O-GlcNAcylation and mTORC1 is linked to T2D and the failure of insulin-producing β-cells. However, the nature of their crosstalk in β-cells remains unexplored. Recently, O-GlcNAcylation, a post-translation modification controlled by enzymes OGT/OGA, emerged as a pivotal regulator for β-cell health; deficiency in either enzyme causes β-cell failure. The present study investigates the previously unidentified connection between nutrient sensor OGT and mTORC1 crosstalk to regulate β-cell mass and function in vivo. We show reduced OGT and mTORC1 activity in islets of preclinical β-cell dysfunction model and obese human islets. Using loss or gain of function of OGT, we identified that O-GlcNAcylation positively regulates mTORC1 signaling in β-cells. O-GlcNAcylation negatively modulates autophagy, as the removal of OGT increases autophagy, while the deletion of OGA decreases it. Increasing mTORC1 signaling, via deletion of TSC2, alleviates the diabetic phenotypes by increasing β-cell mass but not β-cell function in OGT deficient mice. Downstream phospho-protein signaling analysis reveal diverging impact on MKK4 and calmodulin signaling between islets with OGT, TSC2, or combined deletion. These data provide new evidence of OGT's significance as an upstream regulator of mTORC1 and autophagy, crucial for the regulation of β-cell function and glucose homeostasis.
    Keywords:  Autophagy; Beta cells; Diabetes; Endocrinology; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.183033
  16. bioRxiv. 2024 Sep 26. pii: 2024.09.24.614842. [Epub ahead of print]
    Bulk and selective autophagy cooperate to remodel a fungal proteome in response to changing nutrient availability.
    Bertina Telusma, Jean-Claude Farre, Danica S Cui, Suresh Subramani, Joseph H Davis.
      Cells remodel their proteomes in response to changing environments by coordinating changes in protein synthesis and degradation. In yeast, such degradation involves both proteasomal and vacuolar activity, with a mixture of bulk and selective autophagy delivering many of the vacuolar substrates. Although these pathways are known to be generally important for such remodeling, their relative contributions have not been reported on a proteome-wide basis. To assess this, we developed a method to pulse-label the methylotrophic yeast Komagataella phaffii ( i . e. Pichia pastoris ) with isotopically labeled nutrients, which, when coupled to quantitative proteomics, allowed us to globally monitor protein degradation on a protein-by-protein basis following an environmental perturbation. Using genetic ablations, we found that a targeted combination of bulk and selective autophagy drove the vast majority of the observed proteome remodeling activity, with minimal non-autophagic contributions. Cytosolic proteins and protein complexes, including ribosomes, were degraded via Atg11-independent bulk autophagy, whereas proteins targeted to the peroxisome and mitochondria were primarily degraded in an Atg11-dependent manner. Notably, these degradative pathways were independently regulated by environmental cues. Taken together, our new approach greatly increases the range of known autophagic substrates and highlights the outsized impact of autophagy on proteome remodeling. Moreover, the resulting datasets, which we have packaged in an accessible online database, constitute a rich resource for identifying proteins and pathways involved in fungal proteome remodeling.
    DOI:  https://doi.org/10.1101/2024.09.24.614842
  17. J Cancer Res Clin Oncol. 2024 Oct 12. 150(10): 456
    SCYL1-mediated regulation of the mTORC1 signaling pathway inhibits autophagy and promotes gastric cancer metastasis.
    Zihao Zhao, Jinlong Liu, Xian Gao, Zhuzheng Chen, Yilin Hu, Junjie Chen, Weijie Zang, Wanjiang Xue.
       BACKGROUND: The SCY1-like (SCYL) family has been reported to be closely related to cancer metastasis, but it has not been reported in gastric cancer (GC), and its specific mechanism is not clear.
    METHODS: We utilized databases like Deepmap, TCGA, and GEO to identify SCYL1's role in GC. Clinical samples were analyzed for SCYL1 expression and its correlation with patient prognosis. In vitro and in vivo experiments were conducted to assess SCYL1's function in GC cell migration, invasion, and autophagy.
    RESULTS: SCYL1 showed an increased expression in GC tissues, which correlated with a negative prognosis. In vitro experiments demonstrated that SCYL1 promotes GC cell migration and invasion and inhibits autophagy. GSEA indicated an inverse relationship between SCYL1 and autophagy, while a direct relationship was observed with the mTORC1 signaling pathway. Knockdown of SCYL1 enhanced autophagy, while activation of mTORC1 reversed this effect.
    CONCLUSIONS: SCYL1 is a significant contributor to GC progression, promoting metastasis by activating the mTORC1 signaling pathway and inhibiting autophagy. These findings suggest SCYL1 as a potential therapeutic target for GC treatment.
    Keywords:  Autophagy; Gastric cancer; Metastasis; SCYL1; mTORC1
    DOI:  https://doi.org/10.1007/s00432-024-05938-5
  18. Biochim Biophys Acta Mol Cell Res. 2024 Oct 07. pii: S0167-4889(24)00203-9. [Epub ahead of print] 119860
    Atrial natriuretic peptide (ANP) modulates stress-induced autophagy in endothelial cells.
    Maurizio Forte, Simona Marchitti, Flavio di Nonno, Donatella Pietrangelo, Rosita Stanzione, Maria Cotugno, Luca D'Ambrosio, Alessandra D'Amico, Vittoria Cammisotto, Gianmarco Sarto, Erica Rocco, Beatrice Simeone, Sonia Schiavon, Daniele Vecchio, Roberto Carnevale, Salvatore Raffa, Giacomo Frati, Massimo Volpe, Sebastiano Sciarretta, Speranza Rubattu.
      Atrial natriuretic peptide (ANP), a cardiac hormone involved in the regulation of water/sodium balance and blood pressure, is also secreted by endothelial cells, where it exerts protective effects in response to stress. Autophagy is an intracellular self-renewal process involved in the degradation of dysfunctional cytoplasmic elements. ANP was recently reported to act as an extracellular regulator of cardiac autophagy. However, its role in the regulation of endothelial autophagy has never been investigated. Here, we tested the effects of ANP in the regulation of autophagy in human umbilical vein endothelial cells (HUVECs). We found that ANP rapidly increases autophagy and autophagic flux at physiological concentrations through its predominant pathway, mediated by natriuretic peptide receptor type A (NPR-A) and protein kinase G (PKG). We further observed that ANP is rapidly secreted by HUVEC under stress conditions, where it mediates stress-induced autophagy through autocrine and paracrine mechanisms. Finally, we found that the protective effects of ANP in response to high-salt loading or tumor necrosis factor (TNF)-α are blunted by concomitant inhibition of autophagy. Overall, our results suggest that ANP acts as an endogenous autophagy activator in endothelial cells. The autophagy mechanism mediates the protective endothelial effects exerted by ANP.
    Keywords:  Atrial natriuretic peptide; Autophagy; Endothelial dysfunction; Endothelial recovery; Natriuretic peptides
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119860
  19. Geroscience. 2024 Oct 09.
    Hyperactive mTORC1/4EBP1 signaling dysregulates proteostasis and accelerates cardiac aging.
    Weronika Zarzycka, Kamil A Kobak, Catherine J King, Frederick F Peelor, Benjamin F Miller, Ying Ann Chiao.
      The mechanistic target of rapamycin complex 1 (mTORC1) has a major impact on aging by regulation of proteostasis. It is well established that mTORC1 signaling is hyperactivated with aging and age-related diseases. Previous studies have shown that partial inhibition of mTOR signaling by rapamycin reverses age-related deteriorations in cardiac function and structure in old mice. However, the downstream signaling pathways involved in this protection against cardiac aging have not been established. mTORC1 phosphorylates 4E-binding protein 1 (4EBP1) to promote the initiation of cap-dependent translation. The objective of this project is to examine the role of the mTORC1/4EBP1 axis in age-related cardiac dysfunction. We used a whole-body 4EBP1 KO mouse model, which mimics a hyperactive mTORC1/4EBP1/eIF4E axis, to investigate the effects of hyperactive mTORC1/4EBP1 axis in cardiac aging. Echocardiographic measurements of middle-aged 4EBP1 KO mice show impaired diastolic function and myocardial performance compared to age-matched WT mice and these parameters are at similar levels as old WT mice, suggesting that 4EBP1 KO mice experience accelerated cardiac aging. Old 4EBP1 KO mice show further decline in systolic and diastolic function compared to middle-aged counterparts and have worse systolic and diastolic function than age-matched WT mice. Gene expression levels of heart failure markers are not different between 4EBP1 KO and WT hearts. However, ribosomal biogenesis and protein ubiquitination are significantly increased in 4EBP1 KO hearts when compared to WT controls, suggesting dysregulated proteostasis in 4EBP1 KO hearts. Together, these results show that a hyperactive mTORC1/4EBP1 axis accelerates cardiac aging, potentially by dysregulating proteostasis.
    Keywords:  4EBP1; Cardiac aging; Proteostasis; mTOR
    DOI:  https://doi.org/10.1007/s11357-024-01368-w
  20. Sci Signal. 2024 10 08. 17(857): eads1228
    A Siah3 of relief: A role for mitophagy as a fail-safe during developmental axon pruning.
    Rina L Davidson, David J Simon.
      Developmental axon pruning is controlled by a careful balance of pro- and anti-apoptotic signals, which are activated in response to external cues to sculpt mature neuronal circuitry. In this issue of Science Signaling, Abraham et al. define a safeguard against apoptotic axon pruning and illustrate that Siah3 represses Parkin-mediated mitophagy to control the availability of axonal mitochondria that activate the pruning process.
    DOI:  https://doi.org/10.1126/scisignal.ads1228
  21. FASEB J. 2024 Oct 15. 38(19): e70075
    Advances in natural products modulating autophagy influenced by cellular stress conditions and their anticancer roles in the treatment of ovarian cancer.
    Dongxiao Li, Danbo Geng, Min Wang.
      Autophagy is a conservative catabolic process that typically serves a cell-protective function. Under stress conditions, when the cellular environment becomes unstable, autophagy is activated as an adaptive response for self-protection. Autophagy delivers damaged cellular components to lysosomes for degradation and recycling, thereby providing essential nutrients for cell survival. However, this function of promoting cell survival under stress conditions often leads to malignant progression and chemotherapy resistance in cancer. Consequently, autophagy is considered a potential target for cancer therapy. Herein, we aim to review how natural products act as key modulators of autophagy by regulating cellular stress conditions. We revisit various stressors, including starvation, hypoxia, endoplasmic reticulum stress, and oxidative stress, and their regulatory relationship with autophagy, focusing on recent advances in ovarian cancer research. Additionally, we explore how polyphenolic compounds, flavonoids, alkaloids, terpenoids, and other natural products modulate autophagy mediated by stress responses, affecting the malignant biological behavior of cancer. Furthermore, we discuss their roles in ovarian cancer therapy. This review emphasizes the importance of natural products as valuable resources in cancer therapeutics, highlighting the need for further exploration of their potential in regulating autophagy. Moreover, it provides novel insights and potential therapeutic strategies in ovarian cancer by utilizing natural products to modulate autophagy.
    Keywords:  autophagy; natural products; ovarian cancer; stress
    DOI:  https://doi.org/10.1096/fj.202401409R
  22. Neurosurg Rev. 2024 Oct 08. 47(1): 741
    Transcription factor EB (TFEB) promotes autophagy in early brain injury after subarachnoid hemorrhage in rats.
    Wenqi Lu, Haichao Chu, Chunchen Yang, Xiaoxu Li.
      Subarachnoid hemorrhage (SAH) has high mortality. Early brain injury (EBI) is responsible for unfavorable outcomes for patients with SAH. The protective involvement of autophagy in hemorrhagic stroke has been proposed. The transcription factor EB (TFEB) can increase autophagic flux by promoting autophagosome formation and autophagosome-lysosome fusion, and dysregulation of TFEB activity might induce the development of several diseases. However, the biological functions of TFEB in EBI after SAH remain unknown. We established an animal model of SAH by the modified endovascular perforation method. Expression of TFEB and autophagy required genes was measured by western blotting and immunofluorescence staining. SAH grading, brain water content and neurobehavioral functions were evaluated at 24 h post-SAH. Neuronal apoptosis in cerebral cortex was assessed by TUNEL staining and Fluoro Jade B staining. TFEB was downregulated in SAH rats, and its overexpression reduced brain edema and ameliorated neurological deficits of SAH rats. Additionally, the neuronal apoptosis induced by SAH was inhibited by TFEB overexpression. Moreover, TFEB overexpression promoted autophagy after SAH. TFEB overexpression promotes autophagy to inhibit neuronal apoptosis, brain edema and neurological deficits post-SAH.
    Keywords:  Apoptosis; Autophagy; Neurologic deficits; Subarachnoid hemorrhage; TFEB
    DOI:  https://doi.org/10.1007/s10143-024-02879-y
  23. ACS Biomater Sci Eng. 2024 Oct 05.
    DNA Nanotechnology for Application in Targeted Protein Degradation.
    Yang Xiao, Xinyi Guo, Weiwei Zhang, Lequn Ma, Kewei Ren.
      DNA is a kind of flexible and versatile biomaterial for constructing nanostructures and nanodevices. Due to high biocompatibility and programmability and easy modification and fabrication, DNA nanotechnology has emerged as a powerful tool for application in intracellular targeted protein degradation. In this review, we summarize the recent advances in the design and mechanism of targeted protein degradation technologies such as protein hydrolysis targeted chimeras, lysosomal targeted chimeras, and autophagy based protein degradation. Subsequently, we introduce the DNA nanotechnologies of DNA cascade circuits, DNA nanostructures, and dynamic machines. Moreover, we present the latest developments in DNA nanotechnologies in targeted protein degradation. Finally, the vision and challenges are discussed.
    Keywords:  DNA nanotechnology; autophagy based protein degradation; hydrolysis targeted chimera; lysosomal targeted chimera
    DOI:  https://doi.org/10.1021/acsbiomaterials.4c01351
  24. Autophagy. 2024 Oct 10. 1-2
    In vitro and in vivo reconstitution systems reveal the membrane remodeling ability of LC3B and ATG16L1 to form phagophore-like membrane cups.
    Ge Yu, Daniel J Klionsky.
      Macroautophagy/autophagy is a conserved pathway allowing the cell to clear and recycle unwanted materials. While decades of research have revealed molecular players and their hierarchical relationships in autophagy, the detailed mechanism by which these molecules function remains largely unknown. In a recent study, Jagan et al. revealed the membrane remodeling ability of two important proteins, MAP1LC3B/LC3B and ATG16L1, in autophagy. LC3B and the ATG12-ATG5-ATG16L1 complex function synergically to induce the formation of phagophore-like membrane cups on membranes both in vitro and in vivo. In addition, the authors showed that the recently characterized C-terminal membrane-binding domain of ATG16L1 is required for the cup formation and the subsequent transition to autophagic vesicles. Together this research provides more insight into the molecular function of LC3B and ATG16L1, as well as a possible mechanism for phagophore biogenesis.
    Keywords:  ATG16L1; LC3B; autophagy; macroautophagy; membrane remodeling; phagophore biogenesis
    DOI:  https://doi.org/10.1080/15548627.2024.2406127
  25. Mol Cancer. 2024 Oct 11. 23(1): 227
    Chaperone-mediated autophagy modulates Snail protein stability: implications for breast cancer metastasis.
    Ki-Jun Ryu, Ki Won Lee, Seung-Ho Park, Taeyoung Kim, Keun-Seok Hong, Hyemin Kim, Minju Kim, Dong Woo Ok, Gu Neut Bom Kwon, Young-Jun Park, Hyuk-Kwon Kwon, Cheol Hwangbo, Kwang Dong Kim, J Eugene Lee, Jiyun Yoo.
      Breast cancer remains a significant health concern, with triple-negative breast cancer (TNBC) being an aggressive subtype with poor prognosis. Epithelial-mesenchymal transition (EMT) is important in early-stage tumor to invasive malignancy progression. Snail, a central EMT component, is tightly regulated and may be subjected to proteasomal degradation. We report a novel proteasomal independent pathway involving chaperone-mediated autophagy (CMA) in Snail degradation, mediated via its cytosolic interaction with HSC70 and lysosomal targeting, which prevented its accumulation in luminal-type breast cancer cells. Conversely, Snail predominantly localized to the nucleus, thus evading CMA-mediated degradation in TNBC cells. Starvation-induced CMA activation downregulated Snail in TNBC cells by promoting cytoplasmic translocation. Evasion of CMA-mediated Snail degradation induced EMT, and enhanced metastatic potential of luminal-type breast cancer cells. Our findings elucidate a previously unrecognized role of CMA in Snail regulation, highlight its significance in breast cancer, and provide a potential therapeutic target for clinical interventions.
    Keywords:  Breast cancer; Chaperone-mediated autophagy; EMT; Metastasis; Snail
    DOI:  https://doi.org/10.1186/s12943-024-02138-0
  26. Cancer Pathog Ther. 2024 Oct;2(4): 231-245
    Autophagy as a targeted therapeutic approach for skin cancer: Evaluating natural and synthetic molecular interventions.
    Md Liakot Ali, Amdad Hossain Roky, S M Asadul Karim Azad, Abdul Halim Shaikat, Jannatul Naima Meem, Emtiajul Hoque, Abu Mohammed Fuad Ahasan, Mohammed Murshedul Islam, Md Saifur Rahaman Arif, Md Saqline Mostaq, Md Zihad Mahmud, Mohammad Nurul Amin, Md Ashiq Mahmud.
      Skin cancer, a prevalent malignancy worldwide, poses significant health concerns owing to its increasing incidence. Autophagy, a natural cellular process, is a pivotal event in skin cancer and has advantageous and detrimental effects. This duality has prompted extensive investigations into medical interventions targeting autophagy modulation for their substantial therapeutic potential. This systematic review aimed to investigate the relationship between skin cancer and autophagy and the contribution and mechanism of autophagy modulators in skin cancer. We outlined the effectiveness and safety of targeting autophagy as a promising therapeutic strategy for the treatment of skin cancer. This comprehensive review identified a diverse array of autophagy modulators with promising potential for the treatment of skin cancer. Each of these compounds demonstrates efficacy through distinct physiological mechanisms that have been elucidated in detail. Interestingly, findings from a literature search indicated that none of the natural, synthetic, or semisynthetic compounds exhibited notable adverse effects in either human or animal models. Consequently, this review offers novel mechanistic and therapeutic perspectives on the targeted modulation of autophagy in skin cancer.
    Keywords:  Autophagy; Autophagy inducers; Autophagy inhibitors; Nature-derived compounds; Skin cancer; Synthetic compounds
    DOI:  https://doi.org/10.1016/j.cpt.2024.01.002
  27. Med Oncol. 2024 Oct 05. 41(11): 258
    DDX3X dynamics, glioblastoma's genetic landscape, therapeutic advances, and autophagic interplay.
    Arpit Sharma, Shruti S Raut, Alok Shukla, Shivani Gupta, Amit Singh, Abha Mishra.
      Glioblastoma is one of the most aggressive and deadly forms of cancer, posing significant challenges for the medical community. This review focuses on key aspects of Glioblastoma, including its genetic differences between primary and secondary types. Temozolomide is a major first-line treatment for Glioblastoma, and this article explores its development, how it works, and the issue of resistance that limits its effectiveness, prompting the need for new treatment strategies. Gene expression profiling has greatly advanced cancer research by revealing the molecular mechanisms of tumors, which is essential for creating targeted therapies for Glioblastoma. One important protein in this context is DDX3X, which plays various roles in cancer, sometimes promoting it or otherwise suppressing it. Additionally, autophagy, a process that maintains cellular balance, has complex implications in cancer treatment. Understanding autophagy helps to identify resistance mechanisms and potential treatments, with Chloroquine showing promise in treating Glioblastoma. This review covers the interplay between Glioblastoma, DDX3X, and autophagy, highlighting the challenges and potential strategies in treating this severe disease.
    Keywords:   DDX3X ; Autophagy; Chloroquine and resistance; Glioblastoma multiforme; Temozolomide
    DOI:  https://doi.org/10.1007/s12032-024-02525-z
  28. Commun Biol. 2024 Oct 11. 7(1): 1305
    KIF1C facilitates retrograde transport of lysosomes through Hook3 and dynein.
    Takeshi Saji, Mitsuharu Endo, Yasushi Okada, Yasuhiro Minami, Michiru Nishita.
      Lysosomes, crucial cellular organelles, undergo bidirectional transport along microtubules, mediated by motor proteins such as cytoplasmic dynein-1 (dynein) and various kinesins. While the kinesin-3 family member KIF1C is established in mediating anterograde vesicle transport, its role in lysosomal transport remains unclear. Our study reveals that KIF1C unexpectedly supports the retrograde transport of lysosomes, driven by dynein, and contributes to their perinuclear localization. Notably, while KIF1C facilitates this perinuclear positioning, its motor activity is not required and, instead, exerts an inhibitory effect on this process. Mechanistically, KIF1C facilitates this process by interacting with the dynein-activating adaptor Hook3, which associates with the lysosome-anchored protein RUFY3. This regulatory mechanism is critical for the efficient degradation of cargo in autophagic and endocytic pathways. Our findings identify an unconventional, non-motor role for KIF1C in activating dynein-driven lysosomal transport, expanding our understanding of its functional diversity in cellular trafficking.
    DOI:  https://doi.org/10.1038/s42003-024-07023-6
  29. bioRxiv. 2024 Sep 26. pii: 2024.09.24.614781. [Epub ahead of print]
    The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
    Kentson Lam, Yoon Joon Kim, Carlo M Ong, Andrea Z Liu, Fanny J Zhou, Mary Jean Sunshine, Bernadette A Chua, Silvia Vicenzi, Pierce W Ford, Jie-Hua Zhou, Yuning Hong, Eric J Bennett, Leslie A Crews, Edward D Ball, Robert A J Signer.
      Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation of HSF1 sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survival in vivo . Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed AML cells, and significantly reduced AML burden and extended survival in vivo . Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
    DOI:  https://doi.org/10.1101/2024.09.24.614781
  30. Heliyon. 2024 Oct 15. 10(19): e37589
    miRNA375-3p/rapamycin mediates the mTOR pathway by decreasing PS1, enhances microglial cell activity to regulate autophagy in Alzheimer's disease.
    Yuxiang Wang, Zixuan Xiao, Hanlan Yin, Zhichao Ren, Xueting Ma, Yibo Wang, Yan Zhang, Xueqi Fu, Fuqiang Zhang, Linlin Zeng.
      The clinical prevention, diagnosis, treatment, and drug development of Alzheimer's disease (AD) require urgent detection of novel targets and methods. Autophagy and microglia are significantly associated with the pathogenesis of early AD. This study indicated that microRNA-375-3p can inhibit autophagy by promoting mTOR phosphorylation in normal physiological conditions, while microRNA-375-3p promoted autophagy and enhanced neural repair by inhibiting the expression of presenilin 1 in early AD pathogenesis. Furthermore, co-treatment of rapamycin, and microRNA-375-3p can synergistically promote the autophagy and microglial activation in a neuroprotective manner, clear Aβ accumulation, repair nerve damage, and alleviate cognitive dysfunction and memory defects in APP/PS1 TG mice. This research revealed the impact and mechanism of miR375-3p on the early stage of AD through in vivo and in vitro experiments and provides new ideas and directions for the early treatment of AD.
    Keywords:  Alzheimer's disease; Autophagy; Microglia activation; microRNA-375-3p
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37589
  31. Biomol Ther (Seoul). 2024 Oct 07.
    Regulatory Mechanisms Governing the Autophagy-Initiating VPS34 Complex and Its inhibitors.
    Yongook Lee, Nguyen Minh Tuan, Gi Jeong Lee, Boram Kim, Jung Ho Park, Chang Hoon Lee.
      VPS34 is a crucial protein in cells, essential for handling cellular stress through its involvement in autophagy and endocytosis. This protein functions as a Class III phosphatidylinositol 3-kinase, producing phosphatidylinositol 3-phosphate, which is necessary for autophagy and vesicle trafficking. Additionally, VPS34 forms two mutually exclusive complexes, each playing a vital role in autophagy and endocytic sorting. These complexes share common subunits, including VPS15, VPS34, and Beclin 1, with complex I having ATG14 as a specific subunit. Due to its association with various human diseases, regulation of the VPS34 complex I has garnered significant interest, emerging as a potential therapeutic target for drug discovery. Summaries of the structure, function of VPS34 complexes, and developed VPS34 inhibitors have been provided, along with discussions on the regulation mechanism of VPS34, particularly in relation to the initiation complex I of autophagy. This offers valuable insights for treating autophagy-related diseases.
    Keywords:  ATG14; Autophagy; Beclin 1; VPS15; VPS34; VPS34 Inhibitors
    DOI:  https://doi.org/10.4062/biomolther.2024.094
  32. Free Radic Biol Med. 2024 Oct 05. pii: S0891-5849(24)00960-2. [Epub ahead of print]225 181-192
    CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction.
    Ji Hyun Lee, Kyu Hwa Seo, Ji Hye Yang, Sam Seok Cho, Na Yeon Kim, Ji Hye Kim, Kyu Min Kim, Sung Hwan Ki.
      Hepatic stellate cells (HSCs) are primary cells for development and progression of liver fibrosis. Mitophagy is an essential lysosomal process for mitochondrial homeostasis, which can be activated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a representative mitochondrial uncoupler. However, little information is available on the role of CCCP-mediated mitophagy in HSC activation and liver fibrogenesis. In this study, we showed that CCCP treatment in HSCs caused mitochondrial dysfunction proved by decreased mitochondrial membrane potential, mitochondrial DNA, and ATP contents and increased mitochondrial ROS. Moreover, CCCP induced mitophagy and impaired mitophagy flux at the later stage. This blockade of mitophagic flux effect was mediated by suppression of lysosomal activity; CCCP decreased expression of lysosomal markers and cathepsin B activity, and increased lysosomal pH. Intriguingly, CCCP treatment in LX-2 cells or primary HSCs elevated plasminogen activator inhibitor-1 (PAI-1), a typical fibrogenic marker of HSCs which was attenuated by mitochondrial division inhibitor 1, a mitophagy inhibitor. The up-regulation of PAI-1 by CCCP was not due to altered transcriptional activity but lysosomal dysfunction. In vivo acute or sub-chronic treatment of CCCP to mice induced mitophagy and fibrogenesis of liver. Hepatic fibrogenic marker (PAI-1) was incremented with mitophagy markers (parkin and PTEN-induced putative kinase 1) in the livers of CCCP injected mice. Furthermore, we found that 5-aminoimidazole-4-carboxyamide ribonucleoside reversed CCCP-mediated mitophagy and subsequent HSC activation. To conclude, CCCP facilitated HSC activation and hepatic fibrogenesis via mitochondrial dysfunction and lysosomal blockade, implying that attenuation of CCCP-related signaling molecules may contribute to treat liver fibrosis.
    Keywords:  AICAR; CCCP; Hepatic stellate cell; Liver fibrosis; Lysosome
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.259
  33. Mol Cell Proteomics. 2024 Oct 08. pii: S1535-9476(24)00144-0. [Epub ahead of print] 100854
    Proteomic characterization of ubiquitin carboxyl-terminal hydrolase 19 deficient cells reveals a role for USP19 in secretion of lysosomal proteins.
    Simone Bonelli, Margot Lo Pinto, Yihong Ye, Stephan A Mueller, Stefan F Lichtenthaler, Simone D Scilabra.
      Ubiquitin carboxyl-terminal hydrolase 19 (USP19) is a unique deubiquitinase (DUB), characterized by multiple variants generated by alternative splicing. Several variants bear a C-terminal transmembrane domain that anchors them to the endoplasmic reticulum (ER). Other than regulating protein stability by preventing proteasome degradation, USP19 has been reported to rescue substrates from ER-associated protein degradation (ERAD) in a catalytic-independent manner, promote autophagy and address proteins to lysosomal degradation via endosomal microautophagy. USP19 has recently emerged as the protein responsible for the unconventional secretion of misfolded proteins including Parkinson's disease-associated protein α-synuclein. Despite mounting evidence that USP19 plays crucial roles in several biological processes, the underlying mechanisms are unclear due to lack of information on the physiological substrates of USP19. Herein, we used high-resolution quantitative proteomics to analyze changes in the secretome and cell proteome induced by loss of USP19 to identify proteins whose secretion or turnover is regulated by USP19. We found that ablation of USP19 induced significant proteomic alterations both in and out of the cell. Loss of USP19 impaired the release of several lysosomal proteins, including legumain (LGMN) and several cathepsins. In order to understand the underlaying mechanism, we dissected the USP19-regulated secretion of LGMN in several cell types. We found that LGMN was not a DUB substrate of USP19 and that its USP19-dependent release did not require their direct interaction. LGMN secretion occurred by a mechanism that involved the Golgi apparatus, autophagosome formation and lysosome function. This mechanism resembled the recently described "lysosomal exocytosis", by which lysosomal hydrolases are secreted, when ubiquitination of p62 is increased in cells lacking deubiquitinases such as USP15 and USP17. In conclusion, our proteomic characterization of USP19 has identified a collection of proteins in the secretome and within the cell that are regulated by USP19, which link USP19 to secretion of lysosomal proteins, including LGMN.
    Keywords:  legumain; lysosomal exocytosis; proteomics; secretory autophagy; ubiquitin carboxyl-terminal hydrolase 19; unconventional secretion
    DOI:  https://doi.org/10.1016/j.mcpro.2024.100854
  34. bioRxiv. 2024 Sep 23. pii: 2024.09.22.614256. [Epub ahead of print]
    Lysosomal LRRC8 complex regulates lysosomal pH, morphology and systemic glucose metabolism.
    Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, Nihil Abraham, Juan Hong, Ethan Feng, John D Tranter, David Rawnsley, Haiyan Liu, Kyla M Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E Grueter, E Dale Abel, Andrew W Norris, Abhinav Diwan, Rajan Sah.
      The lysosome integrates anabolic signalling and nutrient-sensing to regulate intracellular growth pathways. The leucine-rich repeat containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signalling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show LRRC8A regulates leucine-stimulated mTOR, lysosome size, number, pH, and expression of lysosomal proteins LAMP2, P62, LC3B, suggesting impaired autophagic flux. Mutating a LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signalling and altered lysosomal morphology and pH observed in LRRC8A KO cells. In vivo , LRRC8A-L706A;L707A KI mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance characterized by reduced skeletal muscle glucose-uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8 mediated metabolic signalling function that regulates lysosomal activity, systemic glucose homeostasis and insulin-sensitivity.
    DOI:  https://doi.org/10.1101/2024.09.22.614256
  35. Sci Rep. 2024 Oct 11. 14(1): 23861
    Pink1/Parkin deficiency alters circulating lymphocyte populations and increases platelet-T cell aggregates in rats.
    Jane E Manganaro, Katy Emanuel, Benjamin G Lamberty, Joseph W George, Kelly L Stauch.
      Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk suggesting targeting the Pink1/Parkin pathway in the periphery might have therapeutic potential.
    Keywords:  B cells; Energetics; Parkin; Pink1; Platelets; T cells
    DOI:  https://doi.org/10.1038/s41598-024-74775-w
  36. Cell Commun Signal. 2024 Oct 10. 22(1): 485
    Loss of mitochondrial Ca2+ response and CaMKII/ERK activation by LRRK2R1441G mutation correlate with impaired depolarization-induced mitophagy.
    Eunice Eun-Seo Chang, Huifang Liu, Zoe Yuen-Kiu Choi, Yasine Malki, Steffi Xi-Yue Zhang, Shirley Yin-Yu Pang, Michelle Hiu-Wai Kung, David B Ramsden, Shu-Leong Ho, Philip Wing-Lok Ho.
       BACKGROUND: Stress-induced activation of ERK/Drp1 serves as a checkpoint in the segregation of damaged mitochondria for autophagic clearance (mitophagy). Elevated cytosolic calcium (Ca2+) activates ERK, which is pivotal to mitophagy initiation. This process is altered in Parkinson's disease (PD) with mutations in leucine-rich repeat kinase 2 (LRRK2), potentially contributing to mitochondrial dysfunction. Pathogenic LRRK2 mutation is linked to dysregulated cellular Ca2+ signaling but the mechanism involved remains unclear.
    METHODS: Mitochondrial damages lead to membrane depolarization. To investigate how LRRK2 mutation impairs cellular response to mitochondrial damages, mitochondrial depolarization was induced by artificial uncoupler (FCCP) in wild-type (WT) and LRRK2R1441G mutant knockin (KI) mouse embryonic fibroblasts (MEFs). The resultant cytosolic Ca2+ flux was assessed using live-cell Ca2+ imaging. The role of mitochondria in FCCP-induced cytosolic Ca2+ surge was confirmed by co-treatment with the mitochondrial sodium-calcium exchanger (NCLX) inhibitor. Cellular mitochondrial quality and function were evaluated by Seahorse™ real-time cell metabolic analysis, flow cytometry, and confocal imaging. Mitochondrial morphology was visualized using transmission electron microscopy (TEM). Activation (phosphorylation) of stress response pathways were assessed by immunoblotting.
    RESULTS: Acute mitochondrial depolarization induced by FCCP resulted in an immediate cytosolic Ca2+ surge in WT MEFs, mediated predominantly via mitochondrial NCLX. However, such cytosolic Ca2+ response was abolished in LRRK2 KI MEFs. This loss of response in KI was associated with impaired activation of Ca2+/calmodulin-dependent kinase II (CaMKII) and MEK, the two upstream kinases of ERK. Treatment of LRRK2 inhibitor did not rescue this phenotype indicating that it was not caused by mutant LRRK2 kinase hyperactivity. KI MEFs exhibited swollen mitochondria with distorted cristae, depolarized mitochondrial membrane potential, and reduced mitochondrial Ca2+ store and mitochondrial calcium uniporter (MCU) expression. These mutant cells also exhibited lower cellular ATP: ADP ratio albeit higher basal respiration than WT, indicating compensation for mitochondrial dysfunction. These defects may hinder cellular stress response and signals to Drp1-mediated mitophagy, as evident by impaired mitochondrial clearance in the mutant.
    CONCLUSIONS: Pathogenic LRRK2R1441G mutation abolished mitochondrial depolarization-induced Ca2+ response and impaired the basal mitochondrial clearance. Inherent defects from LRRK2 mutation have weakened the cellular ability to scavenge damaged mitochondria, which may further aggravate mitochondrial dysfunction and neurodegeneration in PD.
    Keywords:  Calcium-dependent pathways; Cellular stress response; LRRK2 mutation; Mitochondrial dysfunction; Mitophagy; NCLX; Parkinson disease
    DOI:  https://doi.org/10.1186/s12964-024-01844-y
  37. bioRxiv. 2024 Sep 28. pii: 2024.09.28.615015. [Epub ahead of print]
    Bridge-like lipid transfer protein 3A (BLTP3A) is associated with membranes of the late endocytic pathway and is an effector of CASM.
    Michael G Hanna, Hely O Rodriguez Cruz, Kenshiro Fujise, Zhuonging Li, Mara Monetti, Pietro De Camilli.
      Recent studies have identified a family of rod-shaped proteins which includes VPS13 and ATG2 and are thought to mediate unidirectional lipid transport at intracellular membrane contacts by a bridge-like mechanism. Here, we show that one such protein, BLTP3A/UHRF1BP1, associates with VAMP7-positive vesicles via its C-terminal region and anchors them to lysosomes via the binding of its chorein domain containing N-terminal region to Rab7. Upon damage of lysosomal membranes and resulting mATG8 recruitment to their surface by CASM, BLTP3A first dissociates from lysosomes but then reassociates with them via an interaction of its LIR motif with mATG8. Such interaction is mutually exclusive to the binding of BLTP3A to vesicles and leaves its N-terminal chorein domain, i.e. the proposed entry site of lipids into this family of proteins, available for binding to another membrane, possibly the ER. Our findings reveal that BLTP3A is an effector CASM, potentially as part of a mechanism to help repair or minimize lysosome damage by delivering lipids.
    DOI:  https://doi.org/10.1101/2024.09.28.615015
  38. J Cell Sci. 2024 Oct 07. pii: jcs.261810. [Epub ahead of print]
    The lysosomal lipid transporter LIMP-2/SCARB2 is part of lysosome-endoplasmic reticulum STARD3-VAPB-dependent contact sites.
    Sönke Rudnik, Saskia Heybrock, Etienne Coyaud, Zizhen Xu, Dante Neculai, Brian Raught, Viola Oorschot, Cecilia Heus, Judith Klumperman, Paul Saftig.
      SCARB2/LIMP-2 is an abundant lysosomal membrane protein. Previous studies have shown LIMP-2 functions as a virus receptor, a chaperone for lysosomal enzyme targeting, and a lipid transporter. The large luminal domain of LIMP-2 contains a hydrophobic tunnel that enables transport of phospholipids, sphingosine and cholesterol from the lysosomal lumen to the membrane. The question about the fate of the lipids after LIMP-2-mediated transport is largely unexplored. To elucidate whether LIMP-2 is part of contact sites between lysosomes and the endoplasmic reticulum (ER), we performed a proximity-based interaction screen. This revealed that LIMP-2 interacts with the endosomal protein STARD3 and the ER-resident protein VAPB. Using imaging and co-immunoprecipitation, we demonstrated colocalization and physical interaction between LIMP-2 and these proteins. Moreover, we found that interaction of LIMP-2 with VAPB required the presence of STARD3. Our findings suggest that LIMP-2 is part of ER-lysosome contact sites, possibly facilitating cholesterol transport from the lysosomal to the ER membrane. This suggests a novel mechanism for inter-organelle communication and lipid trafficking mediated by LIMP-2.
    Keywords:  Endoplasmic reticulum; LIMP-2; Lysosome; Membrane contact sites; SCARB2; STARD3; VAPB
    DOI:  https://doi.org/10.1242/jcs.261810
  39. Cell Commun Signal. 2024 Oct 08. 22(1): 481
    Elucidating the power of arginine restriction: taming type I interferon response in breast cancer via selective autophagy.
    Apsana Lamsal, Sonja Benedikte Andersen, Ida Johansson, Marie-Catherine Drigeard Desgarnier, Camilla Wolowczyk, Nikolai Engedal, Marina Vietri, Geir Bjørkøy, Miriam S Giambelluca, Kristine Pettersen.
       BACKGROUND: Type I interferons (IFN-I) are potent alarm factors that initiate cancer cell elimination within tumors by the immune system. This critical immune response is often suppressed in aggressive tumors, thereby facilitating cancer immune escape and unfavorable patient outcome. The mechanisms underpinning IFN-I suppression in tumors are incompletely understood. Arginase-1 (ARG1)-expressing immune cells that infiltrate tumors can restrict arginine availability by ARG1-mediated arginine degradation. We hypothesized that arginine restriction suppresses the IFN-I response in tumors.
    METHODS: Comprehensive, unbiased open approach omics analyses, various in vitro techniques, including microscopy, qPCR, immunoblotting, knock-down experiments, and flow cytometry were employed, as well as ex vivo analysis of tumor tissue from mice. Several functional bioassays were utilized to assess metabolic functions and autophagy activity in cancer cells.
    RESULTS: Arginine restriction potently induced expression of selective autophagy receptors, enhanced bulk and selective autophagy and strongly suppressed the IFN-I response in cancer cells in an autophagy-dependent manner.
    CONCLUSION: Our study proposes a mechanism for how tumor-infiltrating immune cells can promote cancer immune escape by dampening the IFN-I response. We suggest ARG1 and autophagy as putative therapeutic targets to activate the IFN-I response in tumors.
    DOI:  https://doi.org/10.1186/s12964-024-01858-6
  40. bioRxiv. 2024 Sep 25. pii: 2024.09.25.614931. [Epub ahead of print]
    SARS-CoV-2 ORF3a Protein Impairs Syncytiotrophoblast Maturation, Alters ZO-1 Localization, and Shifts Autophagic Pathways in Trophoblast Cells and 3D Organoids.
    Deepak Kumar, Rowan M Karvas, Brittany Jones, Eliza McColl, Emily Diveley, Sukanta Jash, Surendra Sharma, Jeannie Kelly, Thorold Theunissen, Indira U Mysorekar.
      SARS-CoV-2 infection poses a significant risk to placental physiology, but its impact on placental homeostasis is not well understood. We and others have previously shown that SARS-CoV-2 can colonize maternal and fetal placental cells, yet the specific mechanisms remain unclear. In this study, we investigate ORF3a, a key accessory protein of SARS-CoV-2 that exhibits continuous mutations. Our findings reveal that ORF3a is present in placental tissue from pregnant women infected with SARS-CoV-2 and disrupts autophagic flux in placental cell lines and 3D stem-cell-derived trophoblast organoids (SCTOs), impairing syncytiotrophoblast differentiation and trophoblast invasion. This disruption leads to protein aggregation in cytotrophoblasts (CTB) and activates secretory autophagy, increasing CD63+ extracellular vesicle secretion, along with ORF3a itself. ORF3a also compromises CTB barrier integrity by disrupting tight junctions via interaction with ZO-1, mediated by its PDZ-binding motif, SVPL. Colocalization of ORF3a and ZO-1 in SARS-CoV-2-infected human placental tissue supports our in vitro findings. Deleting the PDZ binding motif in the ORF3a protein (ORF3a-noPBM mutant) restored proper ZO-1 localization at the cell junctions in an autophagy-independent manner. Lastly, we demonstrate that constitutive ORF3a expression induces SC-TOs to transition towards a secretory autophagy pathway likely via the PBM motif, as the ORF3a-NoPBM mutants showed a significant lack of CD63 expression. This study demonstrates the functional impact of ORF3a on placental autophagy and reveals a new mechanism for the activation of secretory autophagy, which may lead to increased extracellular vesicle secretion. These findings provide a foundation for exploring therapeutic approaches targeting ORF3a, specifically focusing on its PBM region to block its interactions with host cellular proteins and limiting placental impact.
    DOI:  https://doi.org/10.1101/2024.09.25.614931
  41. Int J Biol Macromol. 2024 Oct 05. pii: S0141-8130(24)07118-6. [Epub ahead of print]281(Pt 2): 136309
    A novel strategy to enhance inhibition of Hela cervical cancer by combining Lentinus β-glucan and autophagic flux blockage.
    Shuqian Hu, Yan Meng, Liang Guo, Xiaojuan Xu.
      Lentinus β-D-glucan (LNT), derived from artificially cultured mushrooms of Lentinus edodes, shows an important yet incompletely understood biological functions in cancer. In this work, the chemical structure of the refined LNT comprising a β-D-(1, 6)-branched β-D-(1,3)-glucan was further clarified via 1D- and 2D-NMR with high resolution, and its drug resistance resulted from autophagy in human cervical cancer (CC) Hela cells besides its anti-cancer function were revealed in vitro and in vivo. In detail, LNT destroyed cellular homeostasis by significantly increasing the intracellular Ca2+ levels and promoted autophagic flux in vitro Hela cells, which was found to at least partially depend on the PI3K/Akt/mTOR-mediated pathway by up-regulating LC3-II levels and down-regulating the expression of p62, PI3K, p-Akt, and mTOR in Hela cells-transplanted BALB/c nude mice. In particular, LNT-induced autophagy led to a drug resistance against LNT-induced proliferation inhibition and apoptosis in Hela cells, and the co-treatment of autophagy inhibitors and LNT significantly enhanced the inhibition of Hela cells and tumor growth in vitro and in vivo. Therefore, the combination of LNT and autophagy inhibitors will be a novel therapeutic strategy to reduce the resistance and improve the prognosis of CC patients in the clinical.
    Keywords:  Anti-cervical cancer; Autophagic flux blockage; Cellular homeostasis; Drug resistance; Lentinus β-glucan
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136309
  42. J Mol Biol. 2024 Oct 05. pii: S0022-2836(24)00433-9. [Epub ahead of print] 168811
    Molecular basis of the recognition of the active Rab8a by Optineurin.
    Jing Zhang, Lei Liu, Miao Li, Haobo Liu, Xinyu Gong, Yubin Tang, Yuchao Zhang, Xindi Zhou, Zhiqiao Lin, Hanbo Guo, Lifeng Pan.
      Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitates the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism. Here, using biochemical and structural approaches, we systematically characterize the interaction between OPTN and Rab8a, revealing that OPTN selectively recognizes the GTP-bound active Rab8a through its leucine-zipper domain (LZD). The determined crystal structure of OPTN LZD in complex with the active Rab8a not only elucidates the detailed binding mechanism of OPTN with Rab8a but also uncovers a unique binding mode of Rab8a with its effectors. Furthermore, we demonstrate that the central coiled-coil domain of OPTN and the active Rab8a can simultaneously interact with the TBC domain of TBC1D17 to form a ternary complex. Finally, based on the OPTN LZD/Rab8a complex structure and relevant biochemical analyses, we also evaluate several known ALS-associated mutations found in the LZD of OPTN. Collectively, our findings provide mechanistic insights into the interaction of OPTN with Rab8a, expanding our understanding of the binding modes of Rab8a with its effectors and the potential etiology of diseases caused by OPTN mutations.
    Keywords:  Optineurin; Rab8a; Small GTPase; TBC1D17; Vesicular trafficking
    DOI:  https://doi.org/10.1016/j.jmb.2024.168811
  43. Autophagy. 2024 Oct 09. 1-18
    Autophagy controls neuronal differentiation by regulating the WNT-DVL signaling pathway.
    Vincencius Vidyawan, Lesly Puspita, Virginia Blessy Juwono, Magdalena Deline, Kelvin Pieknell, Mi-Yoon Chang, Sang-Hun Lee, Jae-Won Shim.
      Macroautophagy/autophagy dysregulation is associated with various neurological diseases, including Vici syndrome. We aimed to determine the role of autophagy in early brain development. We generated neurons from human embryonic stem cells and developed a Vici syndrome model by introducing a loss-of-function mutation in the EPG5 gene. Autophagy-related genes were upregulated at the neuronal progenitor cell stage. Inhibition of autolysosome formation with bafilomycin A1 treatment at the neuronal progenitor cell stage delayed neuronal differentiation. Notably, WNT (Wnt family member) signaling may be part of the underlying mechanism, which is negatively regulated by autophagy-mediated DVL2 (disheveled segment polarity protein 2) degradation. Disruption of autolysosome formation may lead to failure in the downregulation of WNT signaling, delaying neuronal differentiation. EPG5 mutations disturbed autolysosome formation, subsequently inducing defects in progenitor cell differentiation and cortical layer generation in organoids. Disrupted autophagy leads to smaller organoids, recapitulating Vici syndrome-associated microcephaly, and validating the disease relevance of our study.Abbreviations: BafA1: bafilomycin A1; co-IP: co-immunoprecipitation; DVL2: dishevelled segment polarity protein 2; EPG5: ectopic P-granules 5 autophagy tethering factor; gRNA, guide RNA; hESC: human embryonic stem cells; KO: knockout; mDA, midbrain dopamine; NIM: neural induction media; NPC: neuronal progenitor cell; qPCR: quantitative polymerase chain reaction; UPS: ubiquitin-proteasome system; WNT: Wnt family member; WT: wild type.
    Keywords:  EPG5; Vici syndrome; WNT signal pathway; human embryonic stem cells; macroautophagy; neuronal differentiation
    DOI:  https://doi.org/10.1080/15548627.2024.2407707
  44. bioRxiv. 2024 Sep 23. pii: 2024.09.23.614531. [Epub ahead of print]
    Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool.
    Eleanor Meader, Morgan T Walcheck, Mindy R Leder, Ran Jing, Paul J Wrighton, Wade W Sugden, Mohamad A Najia, Isaac M Oderberg, Vivian M Taylor, Zachary C LeBlanc, Eleanor D Quenzer, Sung-Eun Lim, George Q Daley, Wolfram Goessling, Trista E North.
      Embryonic hematopoietic stem and progenitor cells (HSPCs) have the unique ability to undergo rapid proliferation while maintaining multipotency, a clinically-valuable quality which currently cannot be replicated in vitro. Here, we show that embryonic HSPCs achieve this state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of Tg(ubi:mitoQC) zebrafish indicate that mitophagy initiates as HSPCs undergo endothelial-to-hematopoietic transition and colonize the caudal hematopoietic tissue (CHT). Knockdown of bnip3lb reduced mitophagy and HSPC numbers in the CHT by promoting myeloid-biased differentiation and apoptosis, which was rescued by anti-oxidant exposure. Conversely, induction of mitophagy enhanced both embryonic HSPC and lymphoid progenitor numbers. Significantly, mitophagy activation improved ex vivo functional capacity of hematopoietic progenitors derived from human-induced pluripotent stem cells (hiPSCs), enhancing serial-replating hematopoietic colony forming potential.
    HIGHLIGHTS: ROS promotes HSPC formation in the dorsal aorta but negatively affects maintenance thereafter.HSPCs colonizing secondary niches control ROS levels via Bnip3lb-directed mitophagy.Mitophagy protects nascent HSPCs from ROS-associated apoptosis and maintains multipotency.Induction of mitophagy enhances long-term hematopoietic potential of iPSC-derived HSPCs.
    DOI:  https://doi.org/10.1101/2024.09.23.614531
  45. Trends Cell Biol. 2024 Oct 07. pii: S0962-8924(24)00185-5. [Epub ahead of print]
    Crosstalk between mitochondria-ER contact sites and the apoptotic machinery as a novel health meter.
    Alvaro Larrañaga-SanMiguel, Nora Bengoa-Vergniory, Hector Flores-Romero.
      Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) function as transient signaling platforms that regulate essential cellular functions. MERCS are enriched in specific proteins and lipids that connect mitochondria and the ER together and modulate their activities. Dysregulation of MERCS is associated with several human pathologies including Alzheimer's disease (AD), Parkinson's disease (PD), and cancer. BCL-2 family proteins can locate at MERCS and control essential cellular functions such as calcium signaling and autophagy in addition to their role in mitochondrial apoptosis. Moreover, the BCL-2-mediated apoptotic machinery was recently found to trigger cGAS-STING pathway activation and a proinflammatory response, a recognized hallmark of these diseases that requires mitochondria-ER interplay. This review underscores the pivotal role of MERCS in regulating essential cellular functions, focusing on their crosstalk with BCL-2 family proteins, and discusses how their dysregulation is linked to disease.
    Keywords:  MAMs; MERCS; apoptosis; cancer; inflammation; neurodegeneration
    DOI:  https://doi.org/10.1016/j.tcb.2024.08.007
  46. J Cell Mol Med. 2024 Oct;28(19): e70076
    LINC00941 is a diagnostic biomarker for lung adenocarcinoma and promotes tumorigenesis through cell autophagy.
    Qin Yang, Xi Yong, Xiaoli Chen, Rong Huang, Xiaolin Wang, Zhengmin Xu, Wei Chen.
      Non-small cell lung cancer (NSCLC) is a lethal malignancy. There is mounting evidence indicating that lncRNAs are crucial players with dual roles as both biomarkers and regulators across various cancers. It was reported that LINC00941 plays a cancer-promoting role in NSCLC. However, its impact on tumour autophagy remains poorly understood. In this study, we developed a risk assessment model and identified an autophagy-related lncRNA LINC00941, which has independent predictive and early diagnostic potential. Using RT-qPCR analysis, we confirmed the upregulation of LINC00941 in tumour tissues and cell lines of human lung adenocarcinoma (LUAD). Functional assays, such as CCK8, colony formation and xenograft models, demonstrated the cancer-promoting activity of LINC00941 both in vitro and in vivo. Further analysis using Western blotting analysis, mRFP-GFP-LC3 double fluorescence lentivirus vector and transmission electron microscopy (TEM) confirmed that the knockdown of LINC00941 triggered autophagy. These results indicate that knockdown of LINC00941 induces autophagy and impairs the proliferation of LUAD. Therefore, we propose LINC00941 as an independent biomarker for early diagnosis as well as a therapeutic target in LUAD.
    Keywords:  LINC00941; PI3K/AKT/mTOR pathway; autophagy; lung adenocarcinoma
    DOI:  https://doi.org/10.1111/jcmm.70076
  47. Curr Res Toxicol. 2024 ;7 100193
    The role of TFEB-mediated autophagy-lysosome dysfunction in manganese neurotoxicity.
    Jiaqiao Lu, Peng Su, Fang Zhao, Kailun Yu, Xunbo Yang, Hui Lv, Diya Wang, Jianbin Zhang.
      Excessive long-term manganese intake can inflict irreversible damage to the nervous system, with a predominant effect on the substantia nigra-striatum pathway. Through a mouse model simulating manganese exposure, we delved into its implications on the central nervous motor system, uncovering autophagy-lysosome dysfunction as a pivotal factor in manganese-induced neurotoxicity. Our research illuminated the molecular mechanisms behind TFEB's role in manganese-triggered neuronal autophagy dysfunction, offering insights into the cellular and molecular mechanisms of manganese-induced abnormal protein accumulation. This study lays a significant theoretical foundation for future endeavors aimed at safeguarding against manganese neurotoxicity. Furthermore, TFEB emerges as a potential early molecular biomarker for manganese exposure, providing a solid basis for preemptive protection and clinical treatment for populations exposed to manganese.
    Keywords:  Autophagy; Lysosome; Manganese neurotoxicity; TFEB
    DOI:  https://doi.org/10.1016/j.crtox.2024.100193
  48. Nat Neurosci. 2024 Oct 08.
    Modeling Parkinson's disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines.
    Armin Bayati, Riham Ayoubi, Adriana Aguila, Cornelia E Zorca, Ghislaine Deyab, Chanshuai Han, Sherilyn Junelle Recinto, Emmanuelle Nguyen-Renou, Cecilia Rocha, Gilles Maussion, Wen Luo, Irina Shlaifer, Emily Banks, Ian McDowell, Esther Del Cid Pellitero, Xue Er Ding, Behrang Sharif, Philippe Séguéla, Moein Yaqubi, Carol X-Q Chen, Zhipeng You, Narges Abdian, Heidi M McBride, Edward A Fon, Jo Anne Stratton, Thomas M Durcan, Patrick C Nahirney, Peter S McPherson.
      Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson's disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-γ or interleukin-1β treatment) or when co-cultured with activated microglia-like cells. Exposure to interferon-γ impairs lysosome function in DA neurons, contributing to LB formation. The knockdown of LAMP2 or the knockout of GBA in conjunction with PFF administration is sufficient for inclusion formation. Finally, we observed that the LB-like inclusions in iPSC-derived DA neurons are membrane bound, suggesting that they are not limited to the cytoplasmic compartment but may be formed due to dysfunctions in autophagy. Together, these data indicate that immune-triggered lysosomal dysfunction may contribute to the development of PD pathology.
    DOI:  https://doi.org/10.1038/s41593-024-01775-4
  49. Cell Signal. 2024 Oct 08. pii: S0898-6568(24)00430-3. [Epub ahead of print] 111457
    GDF15 enhances anoikis resistance and metastasis of gastric cancer through protective autophagy.
    Xinyu Gao, Zhongwei Zhang, Qinyi Li, Guokai Tai, ZhiDong Wang.
      Distant metastasis is a prevalent cause of mortality in gastric cancer (GC) patients. Anoikis, a process that induces cell death when cells get detached from the extracellular matrix (ECM), acts as a barrier to tumor metastasis. To survive in the circulatory system and metastasize, tumor cells must acquire anoikis resistance. It is crucial to identify the molecular processes that cause resistance to anoikis in GC since this might lead to the discovery of novel treatment targets and improve the long-term survival of GC patients. In this study, we employed quantitative proteomics to identify growth differentiation factor 15 (GDF15) as a key factor in GC anoikis resistance. We found that GDF15 enhances protective autophagy, thereby promoting anoikis resistance in GC cells. Furthermore, through DNA pull down assay, activating transcription factor 2 (ATF2) was found to be a critical regulator of GDF15 expression, acting as a transcriptional activator of GDF15. Collectively, these discoveries indicate that ATF2 and GDF15 have great potential as target candidates for developing therapeutic strategies to address the metastasis of GC.
    Keywords:  ATF2; Anoikis; Autophagy; GDF15; Gastric cancer; Metastasis
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111457
  50. Expert Rev Mol Med. 2024 Oct 08. 26 e23
    Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance.
    Niharika, Minal Garg.
      Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.
    Keywords:  autophagy; cancer stemness; therapeutic resistance; tumour microenvironment; tumoural heterogeneity
    DOI:  https://doi.org/10.1017/erm.2024.23
  51. Autoimmunity. 2024 Dec;57(1): 2410192
    TMEM164 promotes ferroptosis by selectively mediating ATG5-dependent autophagosome formation to inhibit the progression of LUAD.
    Yongxiang Su, Lintao Li, Junhai Chen, Chao Gao.
      The study focuses on lung adenocarcinoma (LUAD), a predominant type of lung cancer. Despite advancements in diagnostics and molecular therapies, treatment remains challenging due to its low five-year survival rate. This study aims to investigate the role of the transmembrane protein TMEM164 in ferroptosis and anti-tumor immunity in LUAD, and to evaluate its potential as a therapeutic target. Through cellular experiments (such as QPCR, WB, CCK-8, EdU, Transwell, flow cytometry, CO-IP) and animal model experiments (including HE staining and IHC analysis), the relationship between TMEM164 expression and LUAD progression was explored, with particular attention to its mechanisms in ferroptosis and autophagy. The results show that TMEM164 expression is downregulated in LUAD and is associated with poor prognosis. Increasing TMEM164 expression significantly inhibits cell proliferation, migration, and invasion, while promoting an autophagy process dependent on ATG5 for autophagosome formation, thus facilitating ferroptosis. In mouse models, high TMEM164 expression combined with anti-PD-1 antibodies demonstrated synergistic anti-tumor effects. These findings highlight the critical role of TMEM164 in LUAD, suggesting that modulating TMEM164 expression could open new avenues for LUAD treatment.
    Keywords:  PD-1; TMEM164; autophagy; ferroptosis; tumor immunity
    DOI:  https://doi.org/10.1080/08916934.2024.2410192
  52. Acta Neuropathol. 2024 Oct 11. 148(1): 52
    Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway.
    Nicholas Sweeney, Tae Yeon Kim, Cody T Morrison, Liangping Li, Diana Acosta, Jiawen Liang, Nithin V Datla, Julie A Fitzgerald, Haoran Huang, Xianglan Liu, Gregory Huang Tan, Min Wu, Kate Karelina, Chelsea E Bray, Zachary M Weil, Douglas W Scharre, Geidy E Serrano, Takashi Saito, Takaomi C Saido, Thomas G Beach, Olga N Kokiko-Cochran, Jonathan P Godbout, Gail V W Johnson, Hongjun Fu.
      Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.
    Keywords:  Alzheimer’s disease; Autophagy-lysosome pathway; BAG3; Gliosis; Memory; Synaptic dysfunction; Tau; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s00401-024-02810-1
  53. Theriogenology. 2024 Sep 29. pii: S0093-691X(24)00401-1. [Epub ahead of print]230 322-329
    miR-7 promotes apoptosis and autophagy of granulosa cells by targeting KLF4 via JAK/STAT3 signaling pathway in chickens.
    Yimeng Wei, Xiyu Zhao, Yao Zhang, Can Cui, Shunshun Han, Chaowu Yang, Huadong Yin.
      Granulosa cell (GC) death, which leads to follicular atresia, primarily occurs through apoptosis and autophagy. miRNAs are known to be key regulators of autophagy and apoptosis. Although miR-7 acting as a key regulator of follicular atresia, its precise role in granulosa cell autophagy and apoptosis remains to be fully elucidated. In this study, we found that miR-7 was highly expressed in the follicle based on qPCR analysis. Subsequently, transfection of miR-7 inhibitors and mimics downregulated or upregulated the expression of miR-7 and promoted autophagic and apoptotic processes in chicken follicle granulosa cells. Mechanistically, through dual-luciferase reporter gene assays, we validated that KLF4 is a target gene of miR-7. Contrarily, KLF4 was found to negatively regulate autophagy and apoptosis in follicular granulosa cells as evidenced by genetic intervention of KLF4 silencing and overexpression. Furthermore, JAK/STAT3 signaling pathway was confirmed to mediate the regulation of miR-7-KLF4 axis on GC autophagy and apoptosis. These findings offer evidences of the crucial involvement of the miR-7-KLF4 signaling axis in determining autophagy and apoptosis of GCs. This study could offer an important theoretical basis for the use of molecular-assisted breeding in chickens.
    Keywords:  Apoptosis; Autophagy; JAK/STAT3 pathway; KLF4; miR-7
    DOI:  https://doi.org/10.1016/j.theriogenology.2024.09.032
  54. bioRxiv. 2024 Sep 26. pii: 2024.09.24.614704. [Epub ahead of print]
    Endo-IP and Lyso-IP Toolkit for Endolysosomal Profiling of Human Induced Neurons.
    Frances V Hundley, Miguel A Gonzalez-Lozano, Lena M Gottschalk, Aslan N K Cook, Jiuchun Zhang, Joao A Paulo, J Wade Harper.
      Plasma membrane protein degradation and recycling is regulated by the endolysosomal system, wherein endosomes bud from the plasma membrane into the cytosol and mature into degradative lysosomes. As such, the endolysosomal system plays a critical role in determining the abundance of proteins on the cell surface, influencing cellular identity and function. Highly polarized cells, like neurons, rely on the endolysosomal system for axonal and dendritic specialization and synaptic compartmentalization. The importance of this system to neuronal function is reflected by the prevalence of risk variants in components of the system in several neurodegenerative diseases, ranging from Parkinson's to Alzheimer's disease. Nevertheless, our understanding of endocytic cargo and core endolysosomal machinery in neurons is limited, in part due to technical limitations. Here, we developed a toolkit for capturing EEA1-postive endosomes (Endo-IP) and TMEM192-positive lysosomes (Lyso-IP) in stem cell-derived induced neurons (iNeurons). We demonstrated its utility by revealing the endolysosomal protein landscapes for cortical-like iNeurons and stem cells. This allowed us to globally profile endocytic cargo, identifying hundreds of transmembrane proteins, including neurogenesis and synaptic proteins, as well as endocytic cargo with predicted SNX17 or SNX27 recognition motifs. By contrast, parallel lysosome profiling reveals a simpler protein repertoire, reflecting in part temporally controlled recycling or degradation for many endocytic targets. This system will facilitate mechanistic interrogation of endolysosomal components found as risk factors in neurodegenerative disease.
    DOI:  https://doi.org/10.1101/2024.09.24.614704
  55. ACS Nano. 2024 Oct 08.
    Sonocatalysis Regulates Tumor Autophagy for Enhanced Immunotherapy.
    Yihan Fu, Yuchu He, Xindi Wei, Xuwu Zhang, Wenkang Tu, WeiLi Xue, Zichuang Xu, Zhuo Li, Xiyun Yan, Kelong Fan, Dawei Gao.
      Immunotherapy stands as a groundbreaking strategy for cancer treatment, due to its ability to precisely and safely detect and eradicate tumors. However, the efficacy of immunotherapy is often limited by tumor autophagy, a natural defense mechanism that tumors exploit to resist immune attacks. Herein, we introduce a spatiotemporally controlled method to modulate tumor autophagy via sonocatalysis, aiming to improve immunotherapeutic outcomes. Specifically, we synthesized a tumor-targeting nanocatalyst based on a semiconductor heterojunction composed of Barium Titanate (BTO), Black Phosphorus (BP) integrated with Hyaluronic Acid (HA), referred to as BTO/BP-HA. Compared to traditional catalysts, the heterojunction structure enhances energy band bending and rapid electron-hole separation under ultrasonic stimulation, splitting water to generate H2. This promotes tumor cell apoptosis by inhibiting mitochondrial respiration and induces immunogenic cell death, triggering immune responses to eliminate tumor cells. However, the concurrent activation of autophagy mitigates the cytotoxic effectiveness of nanocatalysts. Within the nanocatalyst, BP undergoes lysosomal degradation to generate PO43-, which subsequently interacts with H+ to generate a conjugated acidic anion, increasing the lysosomal pH. This research ingeniously combines sonocatalysis with tumor autophagy, disrupting the activity of acidic hydrolases to inhibit autophagy, thereby enhancing the immune response and improving the effectiveness of immunotherapy.
    Keywords:  heterojunction; immunotherapy; mitochondria damage; sonocatalysis; tumor autophagy
    DOI:  https://doi.org/10.1021/acsnano.4c08468
  56. Med Oncol. 2024 Oct 07. 41(11): 260
    Regulation of autophagy by non-coding RNAs in human glioblastoma.
    Mehran Molavand, Niloufar Ebrahimnezhade, Arash Kiani, Bahman Yousefi, Ahmad Nazari, Maryam Majidinia.
      Glioblastoma, a lethal form of brain cancer, poses substantial challenges in treatment due to its aggressive nature and resistance to standard therapies like radiation and chemotherapy. Autophagy has a crucial role in glioblastoma progression by supporting cellular homeostasis and promoting survival under stressful conditions. Non-coding RNAs (ncRNAs) play diverse biological roles including, gene regulation, chromatin remodeling, and the maintenance of cellular homeostasis. Emerging evidence reveals the intricate regulatory mechanisms of autophagy orchestrated by non-coding RNAs (ncRNAs) in glioblastoma. The diverse roles of these ncRNAs in regulating crucial autophagy-related pathways, including AMPK/mTOR signaling, the PI3K/AKT pathway, Beclin1, and other autophagy-triggering system regulation, sheds light on ncRNAs biological mechanisms in the proliferation, invasion, and therapy response of glioblastoma cells. Furthermore, the clinical implications of targeting ncRNA-regulated autophagy as a promising therapeutic strategy for glioblastoma treatment are in the spotlight of ongoing studies. In this review, we delve into our current understanding of how ncRNAs regulate autophagy in glioblastoma, with a specific focus on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), and their intricate interplay with therapy response.
    Keywords:  Autophagy; Glioblastoma; Non-coding RNAs; circRNAs; lncRNAs; miRNAs
    DOI:  https://doi.org/10.1007/s12032-024-02513-3
  57. bioRxiv. 2024 Sep 24. pii: 2024.09.19.613904. [Epub ahead of print]
    Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease.
    Reji Babygirija, Jessica H Han, Michelle M Sonsalla, Ryan Matoska, Mariah F Calubag, Cara L Green, Anna Tobon, Chung-Yang Yeh, Diana Vertein, Sophia Schlorf, Julia Illiano, Yang Liu, Isaac Grunow, Michael J Rigby, Luigi Puglielli, David A Harris, John M Denu, Dudley W Lamming.
      Caloric restriction (CR) is a widely recognized geroprotective intervention that slows or prevents Alzheimer's disease (AD) in animal models. CR is typically implemented via feeding mice a single meal per day; as CR mice rapidly consume their food, they are subject to a prolonged fast between meals. While CR has been shown to improve metabolic and cognitive functions and suppress pathological markers in AD mouse models, the specific contributions of fasting versus calorie reduction remains unclear. Here, we investigated the contribution of fasting and energy restriction to the beneficial effects of CR on AD progression. To test this, we placed 6-month-old 3xTg mice on one of several diet regimens, allowing us to dissect the effects of calories and fasting on metabolism, AD pathology, and cognition. We find that energy restriction alone, without fasting, was sufficient to improve glucose tolerance and reduce adiposity in both sexes, and to reduce Aβ plaques and improve aspects of cognitive performance in females. However, we find that a prolonged fast between meals is necessary for many of the benefits of CR, including improved insulin sensitivity, reduced phosphorylation of tau, decreased neuroinflammation, inhibition of mTORC1 signaling, and activation of autophagy, as well as for the full cognitive benefits of CR. Finally, we find that fasting is essential for the benefits of CR on survival in male 3xTg mice. Overall, our results demonstrate that fasting is required for the full benefits of a CR diet on the development and progression of AD in 3xTg mice, and suggest that both when and how much we eat influences the development and progress of AD.
    DOI:  https://doi.org/10.1101/2024.09.19.613904
  58. BMB Rep. 2024 Oct 08. pii: 6269. [Epub ahead of print]
    Differential roles of N- and C-terminal LIR motifs in the catalytic activity and membrane targeting of RavZ and ATG4B proteins.
    Sang-Won Park, Ju-Hui Park, Haneul Choi, Pureum Jeon, Seung-Hwan Lee, Won-Dong Shin, Hun-Joo Kim, Jin-A Lee, Deok-Jin Jang.
      Mammalian ATG8 proteins (mATG8s) are essential for selective autophagy because they recruit various proteins with LC3- interacting region (LIR) motifs to autophagic membranes. The RavZ protein, secreted by Legionella pneumophila, and mammalian ATG4B possess functional LIR motifs that participate in lipidated mATG8 deconjugation on autophagic membranes. RavZ comprises three functional LIR motifs at the N- and Cterminal sides of its catalytic domain (CAD). This study demonstrated that LIR motifs at the N-terminal side of the CAD of RavZ are involved in autophagic membrane targeting and substrate recognition, while LIR motif at the C-terminal side facilitate autophagic membrane targeting. Our results also revealed that the C-terminal LIR motif in human ATG4B is pivotal in delipidating LC3B-phosphatidylethanolamine (PE), but it plays a minor role in pro-LC3B priming in the cytosol. Therefore, introducing a functional LIR motif to the N-terminal of ATG4B does not affect LC3B-PE delipidation. This study clearly described the position-dependent roles of LIR motifs in RavZ and ATG4B in cellular contexts.
  59. Int Immunopharmacol. 2024 Oct 04. pii: S1567-5769(24)01838-1. [Epub ahead of print]143(Pt 1): 113316
    Dietary glutamine supplementation improves both Th1 and Th17 responses via CARD11-mTORC1 pathway in murine model of atopic dermatitis.
    Junwen Fan, Xiaoming Wang, Yufei Wang, Jingjing Song, Mingxin Chen, Cuiye Weng, Lei Wang, Zailong Chi, Weixi Zhang.
      Glutamine (GLN) is considered an immunomodulatory nutrient, while caspase recruitment domain 11 (CARD11) is a susceptibility locus for atopic dermatitis (AD). T-cell antigen receptor (TCR)-stimulated GLN uptake requires CARD11. However, the specific pathogenesis of AD via GLN uptake remains unclear. This study aimed to elucidate the association between dietary GLN supplementation and the CARD11 pathway in the pathogenesis of AD, focusing on T helper type 1 (Th1) and Th17 cell expression in AD. Herein, wild-type (WT) mice with house dust mite epidermal-sensitized skin exhibited increased expression of interferon-gamma (IFN-gamma) and interleukin (IL)-17, whereas CARD11 deficiency impaired Th1 and Th17 responses at the same site. CARD11 is a key mediator of Th1 and Th17 expression in AD. Additionally, we suppressed mammalian target of rapamycin complex 1 (mTORC1) signaling, downstream of CARD11, to underscore the critical role of CARD11 in mediating Th1 and Th17 expression in AD. Further, dietary supplementation of GLN to CARD11-/- mice restored Th1 and Th17 responses, whereas inflammatory expression was reduced in WT mice, and p-CARD11 expression and mTORC1 signaling activity were increased in JPM50.6 cells and CARD11-/- mice. Upon inhibiting the GLN transporter, alanine-serine-cysteine transporter carrier 2 (ASCT2), we observed that the Th1 and Th17 response in AD was reduced. Conclusively, ASCT2-mediated GLN uptake improves the expression of Th1 and Th17 cells via CARD11-mTORC1 signaling pathway in AD, suggesting the potential of glutamine supplementation for AD treatment.
    Keywords:  ASCT2; Atopic dermatitis; CARD11; Glutamine; Th1; Th17; mTORC1
    DOI:  https://doi.org/10.1016/j.intimp.2024.113316
  60. Autophagy. 2024 Oct 10.
    Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules.
    Sho Matsui, Takeshi Yamamoto, Yoshitsugu Takabatake, Atsushi Takahashi, Tomoko Namba-Hamano, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Jun Nakamura, Shihomi Maeda, Ayumi Matsumoto, Isao Matsui, Motoko Yanagita, Yoshitaka Isaka.
      The renoprotective effects of SLC5A2/SGLT2 (solute carrier 5 (sodium/glucose cotransporter), member 2) inhibitors have recently been demonstrated in non-diabetic chronic kidney disease (CKD), even without overt albuminuria. However, the mechanism underlying this renoprotection is largely unclear. We investigated the renoprotective mechanisms of the SLC5A2 inhibitor empagliflozin with a focus on ALB (albumin) reabsorption and macroautophagy/autophagy in proximal tubules using wild-type or drug-inducible lrp2/Megalin or atg5 knockout mice with high-fat diet (HFD)-induced obesity or 5/6 nephrectomy that elevated intraglomerular pressure without overt albuminuria. Empagliflozin treatment of HFD-fed mice reduced several hallmarks of lipotoxicity in the proximal tubules, such as phospholipid accumulation in the lysosome, inflammation and fibrosis. Empagliflozin, which decreases intraglomerular pressure, not only reduced the HFD-induced increase in ALB reabsorption via LRP2 in the proximal tubules (i.e. total nephron ALB filtration), as assessed by urinary ALB excretion caused by genetic ablation of Lrp2, but also ameliorated the HFD-induced imbalance in circulating ALB-bound fatty acids. Empagliflozin alleviated the HFD-induced increase in autophagic demand and successfully prevented autophagic stagnation in the proximal tubules. Similarly, empagliflozin decreased ALB exposure and autophagic demand in 5/6 nephrectomized mice. Finally, empagliflozin reduced HFD-induced vulnerability to ischemia - reperfusion injury, whereas LRP2 blockade and atg5 ablation separately diminished this effect. Our findings indicate that empagliflozin reduces ALB exposure and prevents autophagic stagnation in the proximal tubules even without overt albuminuria. Autophagy improvement may be critical for the renoprotection mediated by SLC5A2 inhibition.
    Keywords:  Albuminuria; LRP2/Megalin; SLC5A2/SGLT2 inhibitors; autophagic stagnation; lipotoxicity; lysosome
    DOI:  https://doi.org/10.1080/15548627.2024.2410621
  61. Structure. 2024 Sep 26. pii: S0969-2126(24)00381-2. [Epub ahead of print]
    Mechanism of phospho-Ubls' specificity and conformational changes that regulate Parkin activity.
    Dipti Ranjan Lenka, Shradha Chaurasiya, Loknath Ratnakar, Atul Kumar.
      PINK1 and Parkin mutations lead to the early onset of Parkinson's disease. PINK1-mediated phosphorylation of ubiquitin (Ub), ubiquitin-like protein (NEDD8), and ubiquitin-like (Ubl) domain of Parkin activate autoinhibited Parkin E3 ligase. The mechanism of various phospho-Ubls' specificity and conformational changes leading to Parkin activation remain elusive. Herein, we show that compared to Ub, NEDD8 is a more robust binder and activator of Parkin. Structures and biophysical/biochemical data reveal specific recognition and underlying mechanisms of pUb/pNEDD8 and pUbl domain binding to the RING1 and RING0 domains, respectively. Also, pUb/pNEDD8 binding in the RING1 pocket promotes allosteric conformational changes in Parkin's catalytic domain (RING2), leading to Parkin activation. Furthermore, Parkinson's disease mutation K211N in the RING0 domain was believed to perturb Parkin activation due to loss of pUb binding. However, our data reveal allosteric conformational changes due to N211 that lock RING2 with RING0 to inhibit Parkin activity without disrupting pNEDD8/pUb binding.
    Keywords:  NEDD8; PINK1; Parkin; Parkinson's disease; RBR E3 ligase; X-ray crystallography; ubiquitin
    DOI:  https://doi.org/10.1016/j.str.2024.09.012
  62. Pflugers Arch. 2024 Oct 08.
    Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo.
    Maximilian Schiller, Gregory C Wilson, Simone Keitsch, Matthias Soddemann, Barbara Wilker, Michael J Edwards, Norbert Scherbaum, Erich Gulbins.
      Major depressive disorder (MDD) is a common and severe psychiatric disease, which does not only lead to variety of neuropsychiatric symptoms, but unfortunately in a relatively large proportion of cases also to suicide. The pathogenesis of MDD still requires definition. We have previously shown that ceramide is increased in the blood plasma of patients with MDD. In mouse models of MDD, which are induced by treatment with corticosterone or application of chronic unpredictable stress, increased blood plasma ceramide also increased and caused an inhibition of phospholipase D in endothelial cells of the hippocampus and reduced phosphatidic acid levels in the hippocampus. Here, we demonstrated that corticosterone treatment of PC12 cells resulted in reduced cellular autophagy, which is corrected by treatment with phosphatidic acid. In vivo, treatment of mice with corticosterone or chronic unpredictable stress also reduced autophagy in hippocampus neurons. Autophagy was normalized upon i.v. injection of phosphatidic acid in these mouse models of MDD. In an attempt to identify targets of phosphatidic acid in neurons, we demonstrated that corticosterone reduced levels of the ganglioside GM1 in PC-12 cells and the hippocampus of mice, which were normalized by treatment of cells or i.v. injection of mice with phosphatidic acid. GM1 application also normalized autophagy in cultured neurons. Phosphatidic acid and GM1 corrected stress-induced alterations in behavior, i.e., mainly anxiety and anhedonia, in experimental MDD in mice. Our data suggest that phosphatidic acid may regulate via GM1 autophagy in neurons.
    Keywords:  Autophagy; Ceramide; Gangliosides; Major depression; Phosphatidic acid
    DOI:  https://doi.org/10.1007/s00424-024-03026-8
  63. Oncoimmunology. 2024 ;13(1): 2413200
    Acyl CoA binding protein (ACBP): an autophagy checkpoint that can be targeted for improving cancer immunosurveillance.
    Léa Montégut, Isabelle Martins, Guido Kroemer.
      Acyl CoA binding protein (ACBP) encoded by DBI is a tissue hormone that limits autophagy in multiple cell types, hence acting as an extracellular autophagy checkpoint. We recently reported in Molecular Cancer that monoclonal antibodies neutralizing ACBP improve immunosurveillance of breast and lung carcinomas. Moreover, ACBP neutralization improves the outcome of neoadjuvant chemoimmunotherapy with PD-1 blockade in preclinical models.
    Keywords:  Caloric restriction mimetics; chemotherapy; immune checkpoint inhibitor; immunotherapy mammary carcinoma; non-small cell lung cancer
    DOI:  https://doi.org/10.1080/2162402X.2024.2413200
  64. Trends Cell Biol. 2024 Oct 07. pii: S0962-8924(24)00188-0. [Epub ahead of print]
    Cytoplasmic mtDNA clearance suppresses inflammatory immune responses.
    Chenghao Yan, Xu Liu, Haodong Xu, Liming Wang.
      Upon various stresses, mtDNA leaks from mitochondria into the cytoplasm, leading to cellular dysfunction and inflammation, thereby exacerbating disease progression. The autophagy-lysosome pathway has emerged as a pivotal quality control mechanism for eliminating abnormal cytoplasmic mtDNA. This article summarizes the mechanisms underlying mtDNA-triggered inflammation and how cytoplasmic mtDNA is eliminated.
    Keywords:  autophagy–lysosome pathway; cGAS–STING pathway; mtDNA
    DOI:  https://doi.org/10.1016/j.tcb.2024.09.002
  65. Sci Rep. 2024 10 08. 14(1): 23387
    5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage.
    Ankita Dutta, Anuja Chakraborty, Tulika Ghosh, Anoop Kumar.
      5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.
    Keywords:  5–Fluorouracil; Apoptosis; Autophagy; Hepatocellular carcinoma; Reactive oxygen species (ROS); Starvation
    DOI:  https://doi.org/10.1038/s41598-024-73143-y
  66. Cell Death Dis. 2024 Oct 11. 15(10): 743
    Tumor-associated macrophages/C-X-C motif chemokine ligand 1 promotes breast cancer autophagy-mediated chemoresistance via IGF1R/STAT3/HMGB1 signaling.
    Bowen Yang, Guanzhi Li, Shengqi Wang, Yifeng Zheng, Juping Zhang, Bo Pan, Neng Wang, Zhiyu Wang.
      Autophagy-mediated chemoresistance is the core mechanism for therapeutic failure and poor prognosis in breast cancer. Breast cancer chemotherapy resistance is believed to be influenced by tumor-associated macrophages (TAMs), by which C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant cytokine secreted. Yet, its role in mediating autophagy-related chemoresistance is still unknown. This study aimed to explore the molecular mechanisms by which TAMs/CXCL1 induced autophagy-mediated chemoresistance in breast cancer. It was found that TAMs/CXCL1 promoted chemoresistance of breast cancer cells through autophagy activation in vitro, and CXCL1 silence could enhance the chemosensitivity of paclitaxel-resistant breast cancer cells via autophagy inhibition. A high-throughput quantitative PCR chip and subsequent target validation showed that CXCL1 induced autophagy-mediated chemoresistance by inhibiting VHL-mediated IGF1R ubiquitination. The elevated IGF1R then promoted STAT3/HMGB1 signaling to facilitate autophagy. Additionally, TAMs/CXCL1 silence improved paclitaxel chemosensitivity by suppressing autophagy in breast cancer mice xenografts, and clinical studies further linked CXCL1 to IGF1R/HMGB1 signaling, as well as shorter free survival of recurrence. Taken together, these results not only uncover the crucial role of TAMs/CXCL1 signaling in mediating breast cancer chemoresistance through enhancing autophagy, but also shed novel light on the molecular mechanism of IGF1R/STAT3/HMGB1 pathway in regulating autophagy and its impact on cancer prognosis.
    DOI:  https://doi.org/10.1038/s41419-024-07123-5
  67. Inflammation. 2024 Oct 09.
    Interplay of α-Synuclein Oligomers and Endoplasmic Reticulum Stress in Parkinson'S Disease: Insights into Cellular Dysfunctions.
    Hui Zeng, Ye Liu, Xinjie Liu, Jianwei Li, Lixuan Lu, Cheng Xue, Xiao Wu, Xinran Zhang, Zijian Zheng, Guohui Lu.
      Oligomeric forms of α-synuclein (α-syn) are critical in the formation of α-synuclein fibrils, exhibiting neurotoxic properties that are pivotal in the pathogenesis of Parkinson's disease (PD). A salient feature of this pathology is the disruption of the protein folding capacity of the endoplasmic reticulum (ER), leading to a perturbation in the ER's protein quality control mechanisms. The accumulation of unfolded or misfolded proteins instigates ER stress. However, the onset of ER stress and the consequent activation of the Unfolded Protein Response (UPR) and Endoplasmic Reticulum-Associated Degradation (ERAD) pathways do not merely culminate in apoptosis when they fail to restore cellular homeostasis. More critically, this condition initiates a cascade of reactions involving ER-related structures and organelles, resulting in multifaceted cellular damage and, potentially, a feedback loop that precipitates neuroinflammation. In this review, we elucidate the interplay between UPR and ERAD, as well as the intricate crosstalk among the ER and other organelles such as mitochondria, lysosomes, and the Golgi apparatus, underscoring their roles in the neurodegenerative process.
    Keywords:  Alpha-synuclein; Autophagy; Endoplasmic Reticulum Stress; Mitochondria; PD
    DOI:  https://doi.org/10.1007/s10753-024-02156-6
  68. Cell Death Discov. 2024 Oct 11. 10(1): 435
    Glycolysis-mTORC1 crosstalk drives proliferation of patient-derived endometrial cancer spheroid cells with ALDH activity.
    Haruka Ueda, Tatsuya Ishiguro, Yutaro Mori, Kaoru Yamawaki, Koji Okamoto, Takayuki Enomoto, Kosuke Yoshihara.
      Cancer stem cells are associated with aggressive phenotypes of malignant tumors. A prominent feature of uterine endometrial cancer is the activation of the PI3K-Akt-mTOR pathway. In this study, we present variations in sensitivities to a PI3K-Akt-mTORC1 inhibitor among in vitro endometrial cancer stem cell-enriched spheroid cells from clinical specimens. The in vitro sensitivity was consistent with the effects observed in in vivo spheroid-derived xenograft tumor models. Our findings revealed a complementary suppressive effect on endometrial cancer spheroid cell growth with the combined use of aldehyde dehydrogenase (ALDH) and PI3K-Akt inhibitors. In the PI3K-Akt-mTORC1 signaling cascade, the influence of ALDH on mTORC1 was partially channeled through retinoic acid-induced lactate dehydrogenase A (LDHA) activation. LDHA inhibition was found to reduce endometrial cancer cell growth, aligning with the effects of mTORC1 inhibition. Building upon our previous findings highlighting ALDH-driven glycolysis through GLUT1 in uterine endometrial cancer spheroid cells, curbing mTORC1 enhanced glucose transport via GLUT1 activation. Notably, elevated LDHA expression correlated with adverse clinical survival and escalated tumor grade, especially in advanced stages. Collectively, our findings emphasize the pivotal role of ALDH-LDHA-mTORC1 cascade in the proliferation of endometrial cancer. Targeting the interaction between mTORC1 and ALDH-influenced glycolysis holds promise for developing novel strategies to combat this aggressive cancer.
    DOI:  https://doi.org/10.1038/s41420-024-02204-y
  69. Cell Commun Signal. 2024 Oct 09. 22(1): 482
    TMEM132A regulates Wnt/β-catenin signaling through stabilizing LRP6 during mouse embryonic development.
    Shin Ae Oh, Jiyeon Jeon, Su-Yeon Je, Seoyoung Kim, Joohyun Jung, Hyuk Wan Ko.
      The Wnt/β-catenin signaling pathway is crucial for embryonic development and adult tissue homeostasis. Dysregulation of Wnt signaling is linked to various developmental anomalies and diseases, notably cancer. Although numerous regulators of the Wnt signaling pathway have been identified, their precise function during mouse embryo development remains unclear. Here, we revealed that TMEM132A is a crucial regulator of canonical Wnt/β-catenin signaling in mouse development. Mouse embryos lacking Tmem132a displayed a range of malformations, including open spina bifida, caudal truncation, syndactyly, and renal defects, similar to the phenotypes of Wnt/β-catenin mutants. Tmem132a knockdown in cultured cells suppressed canonical Wnt/β-catenin signaling. In developing mice, loss of Tmem132a also led to diminished Wnt/β-catenin signaling. Mechanistically, we showed that TMEM132A interacts with the Wnt co-receptor LRP6, thereby stabilizing it and preventing its lysosomal degradation. These findings shed light on a novel role for TMEM132A in regulating LRP6 stability and canonical Wnt/β-catenin signaling during mouse embryo development. This study provides valuable insights into the molecular intricacies of the Wnt signaling pathway. Further research may deepen our understanding of Wnt pathway regulation and offer its potential therapeutic applications.
    Keywords:  LRP6; Lysosomal degradation; Mouse development; TMEM132A; Wnt/β-catenin signaling
    DOI:  https://doi.org/10.1186/s12964-024-01855-9
  70. J Nanobiotechnology. 2024 Oct 08. 22(1): 608
    Nanomaterial-mediated host directed therapy of tuberculosis by manipulating macrophage autophagy.
    Yilin Liu, Jiajun Wang, Jiayi Yang, Jiaojiao Xia, Jiaqi Yu, Dongsheng Chen, Yuhe Huang, Fen Yang, Yongdui Ruan, Jun-Fa Xu, Jiang Pi.
      Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains a major public health issue worldwide. Mtb has developed complicated strategies to inhibit the immunological clearance of host cells, which significantly promote TB epidemic and weaken the anti-TB treatments. Host-directed therapy (HDT) is a novel approach in the field of anti-infection for overcoming antimicrobial resistance by enhancing the antimicrobial activities of phagocytes through phagosomal maturation, autophagy and antimicrobial peptides. Autophagy, a highly conserved cellular event within eukaryotic cells that is effective against a variety of bacterial infections, has been shown to play a protective role in host defense against Mtb. In recent decades, the introduction of nanomaterials into medical fields open up a new scene for novel therapeutics with enhanced efficiency and safety against different diseases. The active modification of nanomaterials not only allows their attractive targeting effects against the host cells, but also introduce the potential to regulate the host anti-TB immunological mechanisms, such as apoptosis, autophagy or macrophage polarization. In this review, we introduced the mechanisms of host cell autophagy for intracellular Mtb clearance, and how functional nanomaterials regulate autophagy for disease treatment. Moreover, we summarized the recent advances of nanomaterials for autophagy regulations as novel HDT strategies for anti-TB treatment, which may benefit the development of more effective anti-TB treatments.
    Keywords:  Autophagy; Host directed therapy; Macrophage; Nanomaterials; Tuberculosis
    DOI:  https://doi.org/10.1186/s12951-024-02875-w
  71. Front Pharmacol. 2024 ;15 1430469
    Apoptosis, autophagy, ferroptosis, and pyroptosis in cisplatin-induced ototoxicity and protective agents.
    Dingyuan Dai, Chao Chen, Chen Lu, Yu Guo, Qi Li, Chen Sun.
      Cisplatin is widely used to treat various solid tumors. However, its toxicity to normal tissues limits its clinical application, particularly due to its ototoxic effects, which can result in hearing loss in patients undergoing chemotherapy. While significant progress has been made in preclinical studies to elucidate the cellular and molecular mechanisms underlying cisplatin-induced ototoxicity (CIO), the precise mechanisms remain unclear. Moreover, the optimal protective agent for preventing or mitigating cisplatin-induced ototoxicity has yet to be identified. This review summarizes the current understanding of the roles of apoptosis, autophagy, ferroptosis, pyroptosis, and protective agents in cisplatin-induced ototoxicity. A deeper understanding of these cell death mechanisms in the inner ear, along with the protective agents, could facilitate the translation of these agents into clinical therapeutics, help identify new therapeutic targets, and provide novel strategies for cisplatin-based cancer treatment.
    Keywords:  apoptosis; autophagy; cisplatin; ferroptosis; ototoxicity; protective agents; pyroptosis
    DOI:  https://doi.org/10.3389/fphar.2024.1430469
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