bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–02–11
fifty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.
  2. The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs.
  3. Regulation and functions of autophagy during animal development.
  4. Ataxin-2 sequesters Raptor into aggregates and impairs cellular mTORC1 signaling.
  5. A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.
  6. Mechanisms and therapeutic implications of selective autophagy in nonalcoholic fatty liver disease.
  7. RABC1, an Arabidopsis RAB18 regulates binding and subsequent detachment of autophagosomes from the ER in autophagy.
  8. Driving autophagy - the role of molecular motors.
  9. Physiological functions of ULK1/2.
  10. The dual role of autophagy in the regulation of cancer treatment.
  11. ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.
  12. Multiple genes core to ERAD, macro-autophagy and lysosomal degradation pathways participate in the proteostasis response in α1-antitrypsin deficiency.
  13. The Obesity-Autophagy-Cancer Axis: Mechanistic Insights and Therapeutic Perspectives.
  14. Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer.
  15. Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling.
  16. DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins.
  17. Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation.
  18. Rab32 family proteins regulate autophagosomal components recycling.
  19. Advances in the study of autophagy in breast cancer.
  20. Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
  21. Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
  22. Uropathogenic Escherichia coli subverts host autophagic defenses by stalling pre-autophagosomal structures to escape lysosome exocytosis.
  23. p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury.
  24. Three-step docking by WIPI2, ATG16L1, and ATG3 delivers LC3 to the phagophore.
  25. Characterization of ATG8-family protein phosphorylation by Phos-tag gel for autophagy study.
  26. Inhibition of cysteine protease cathepsin Lincreases the level and activity of lysosomal glucocerebrosidase.
  27. Tissue-specific expression differences in Ras-related GTP-binding proteins in male rats.
  28. AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
  29. The Ykt6-Snap29-Syx13 SNARE complex promotes crinophagy via secretory granule fusion with Lamp1 carrier vesicles.
  30. Phosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome.
  31. Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.
  32. Sestrin2 reduces ferroptosis via the Keap1/Nrf2 signaling pathway after intestinal ischemia-reperfusion.
  33. PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
  34. A global bibliometric and visualized analysis of the links between the autophagy and acute myeloid leukemia.
  35. MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.
  36. LRP10 and α-synuclein transmission in Lewy body diseases.
  37. KAT8 is upregulated and recruited to the promoter of Atg8 by FOXO to induce H4 acetylation for autophagy under 20-hydroxyecdysone regulation.
  38. Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth.
  39. Rbpms2 promotes female fate upstream of the nutrient sensing Gator2 complex component, Mios.
  40. DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition.
  41. The role of mTORC1/TFEB axis mediated lysosomal biogenesis and autophagy impairment in fluoride neurotoxicity and the intervention effects of resveratrol.
  42. The interplay between autophagy and apoptosis: its implication in lung cancer and therapeutics.
  43. WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.
  44. Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.
  45. PHGDH knockdown increases sensitivity to SR1, an aryl hydrocarbon receptor antagonist, in colorectal cancer by activating the autophagy pathway.
  46. Role of the Cytosolic Domain of the a3 Subunit of V-ATPase in the Interaction with Rab7 and Secretory Lysosome Trafficking in Osteoclasts.
  47. GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.
  48. Evidence for Involvement of ADP-Ribosylation Factor 6 in Intracellular Trafficking and Release of Murine Leukemia Virus Gag.
  49. Conserved autophagy and diverse cell wall composition: Unifying features of vascular tissues in evolutionarily distinct plants.
  50. Immune checkpoints between epithelial-mesenchymal transition and autophagy: A conflicting triangle.
  51. Lysosomal stress drives the release of pathogenic α-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway.
  52. Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
  53. Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome.
  54. M6A methylation-regulated autophagy may be a new therapeutic target for intervertebral disc degeneration.
  1. FASEB J. 2024 Feb 15. 38(3): e23454
    Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.
    Vitor M Ramos, Julian D C Serna, Eloisa A Vilas-Boas, João Victor Cabral-Costa, Fernanda M Cunha, Tetsushi Kataura, Viktor I Korolchuk, Alicia J Kowaltowski.
      Mitochondria shape intracellular Ca2+ signaling through the concerted activity of Ca2+ uptake via mitochondrial calcium uniporters and efflux by Na+ /Ca2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca2+ , and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation-induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER-phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca2+ levels, and intracellular Ca2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca2+ efflux regulates autophagy through the modulation of Ca2+ signaling. Collectively, our results show that the mitochondrial Ca2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.
    Keywords:  NCLX; autophagy regulation; calcium transport; caloric restriction; hepatocytes; mitochondria
    DOI:  https://doi.org/10.1096/fj.202301368RR
  2. Mol Cell. 2024 Jan 31. pii: S1097-2765(24)00048-0. [Epub ahead of print]
    The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs.
    Shu Yang, Chun-Yuan Ting, Mary A Lilly.
      Lysosomes are central to metabolic homeostasis. The microphthalmia bHLH-LZ transcription factors (MiT/TFEs) family members MITF, TFEB, and TFE3 promote the transcription of lysosomal and autophagic genes and are often deregulated in cancer. Here, we show that the GATOR2 complex, an activator of the metabolic regulator TORC1, maintains lysosomal function by protecting MiT/TFEs from proteasomal degradation independent of TORC1, GATOR1, and the RAG GTPase. We determine that in GATOR2 knockout HeLa cells, members of the MiT/TFEs family are ubiquitylated by a trio of E3 ligases and are degraded, resulting in lysosome dysfunction. Additionally, we demonstrate that GATOR2 protects MiT/TFE proteins in pancreatic ductal adenocarcinoma and Xp11 translocation renal cell carcinoma, two cancers that are driven by MiT/TFE hyperactivation. In summary, we find that the GATOR2 complex has independent roles in TORC1 regulation and MiT/TFE protein protection and thus is central to coordinating cellular metabolism with control of the lysosomal-autophagic system.
    Keywords:  E3 ligases; GATOR2; MiT/TFEs; TORC1; autophagy; lysosome; pancreatic ductal adenocarcinoma; renal cell carcinoma; ubiquitination
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.012
  3. J Mol Biol. 2024 Feb 02. pii: S0022-2836(24)00045-7. [Epub ahead of print] 168473
    Regulation and functions of autophagy during animal development.
    Lucas J Restrepo, Eric H Baehrecke.
      Autophagy is used to degrade cytoplasmic materials, and is critical to maintain cell and organismal health in diverse animals. Here we discuss the regulation, utilization and impact of autophagy on development, including roles in oogenesis, spermatogenesis and embryogenesis in animals. We also describe how autophagy influences postembryonic development in the context of neuronal and cardiac development, wound healing, and tissue regeneration. We describe recent studies of selective autophagy during development, including mitochondria-selective autophagy and endoplasmic reticulum (ER)-selective autophagy. Studies of developing model systems have also been used to discover novel regulators of autophagy, and we explain how studies of autophagy in these physiologically relevant systems are advancing our understanding of this important catabolic process.
    DOI:  https://doi.org/10.1016/j.jmb.2024.168473
  4. FEBS J. 2024 Feb 03.
    Ataxin-2 sequesters Raptor into aggregates and impairs cellular mTORC1 signaling.
    Ya-Jun Liu, Jian-Yang Wang, Xiang-Le Zhang, Lei-Lei Jiang, Hong-Yu Hu.
      Ataxin-2 (Atx2) is a polyglutamine (polyQ) protein, in which abnormal expansion of the polyQ tract can trigger protein aggregation and consequently cause spinocerebellar ataxia type 2 (SCA2), but the mechanism underlying how Atx2 aggregation leads to proteinopathy remains elusive. Here, we investigate the molecular mechanism and cellular consequences of Atx2 aggregation by molecular cell biology approaches. We have revealed that either normal or polyQ-expanded Atx2 can sequester Raptor, a component of mammalian target of rapamycin complex 1 (mTORC1), into aggregates based on their specific interaction. Further research indicates that the polyQ tract and the N-terminal region (residues 1-784) of Atx2 are responsible for the specific sequestration. Moreover, this sequestration leads to suppression of the mTORC1 activity as represented by down-regulation of phosphorylated P70S6K, which can be reversed by overexpression of Raptor. As mTORC1 is a key regulator of autophagy, Atx2 aggregation and sequestration also induces autophagy by upregulating LC3-II and reducing phosphorylated ULK1 levels. This study proposes that Atx2 sequesters Raptor into aggregates, thereby impairing cellular mTORC1 signaling and inducing autophagy, and will be beneficial for a better understanding of the pathogenesis of SCA2 and other polyQ diseases.
    Keywords:  Raptor; aggregation; ataxin-2; mTORC1 signaling; sequestration
    DOI:  https://doi.org/10.1111/febs.17081
  5. Nat Cell Biol. 2024 Feb 05.
    A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.
    A S Gross, R Ghillebert, M Schuetter, E Reinartz, A Rowland, B C Bishop, M Stumpe, J Dengjel, M Graef.
      Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain. Notably, core AKC components Atg13 and Atg17 are dispensable for phosphate starvation-induced autophagy revealing significant compositional and functional plasticity of the AKC. Our data indicate that, instead of functioning as a selective autophagy receptor, Pho81 compensates for partially inactive Atg13 by promoting Atg11 phosphorylation by Atg1 critical for pexophagy during phosphate starvation. Our work shows Atg11/FIP200 adaptor subunits bind not only selective autophagy receptors but also modulator subunits that convey metabolic information directly to the AKC for autophagy regulation.
    DOI:  https://doi.org/10.1038/s41556-024-01348-4
  6. J Adv Res. 2024 Feb 01. pii: S2090-1232(24)00041-9. [Epub ahead of print]
    Mechanisms and therapeutic implications of selective autophagy in nonalcoholic fatty liver disease.
    Suwei Jin, Yujia Li, Tianji Xia, Yongguang Liu, Shanshan Zhang, Hongbo Hu, Qi Chang, Mingzhu Yan.
       BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, whereas there is no approved drug therapy due to its complexity. Studies are emerging to discuss the role of selective autophagy in the pathogenesis of NAFLD, because the specificity among the features of selective autophagy makes it a crucial process in mitigating hepatocyte damage caused by aberrant accumulation of dysfunctional organelles, for which no other pathway can compensate.
    AIM OF REVIEW: This review aims to summarize the types, functions, and dynamics of selective autophagy that are of particular importance in the initiation and progression of NAFLD. And on this basis, the review outlines the therapeutic strategies against NAFLD, in particular the medications and potential natural products that can modulate selective autophagy in the pathogenesis of this disease.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: The critical roles of lipophagy and mitophagy in the pathogenesis of NAFLD are well established, while reticulophagy and pexophagy are still being identified in this disease due to the insufficient understanding of their molecular details. As gradual blockage of autophagic flux reveals the complexity of NAFLD, studies unraveling the underlying mechanisms have made it possible to successfully treat NAFLD with multiple pharmacological compounds that target associated pathways. Overall, it is convinced that the continued research into selective autophagy occurring in NAFLD will further enhance the understanding of the pathogenesis and uncover novel therapeutic targets.
    Keywords:  Autophagic flux; Nonalcoholic fatty liver disease; Selective autophagy; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.jare.2024.01.027
  7. Autophagy. 2024 Feb 07.
    RABC1, an Arabidopsis RAB18 regulates binding and subsequent detachment of autophagosomes from the ER in autophagy.
    Yang Shao, Jiaqi Sun, Hugo Zheng.
      Macroautophagy/autophagy is a strategy cells use to cope with detrimental conditions, e.g. nutrient deficiency. Phagophores, the precursors to autophagosomes, are initiated and expanded on the endoplasmic reticulum (ER). However, how phagophores and completed autophagosomes are linked to the ER remains incompletely understood. We recently unveiled a RAB GTPase-based linkage between the two structures. RABC1 is a plant member of RABC/RAB18 GTPases. Our biochemical and microscopy data indicated that RABC1 promotes autophagy in response to nutrient starvation, but not under ER stress. Under nutrient-starvation conditions, active RABC1 interacts with ATG18a on the ER, controlling the association of ATG18a to the ER. Subsequently, active RABC1 is turned off allowing expanded phagophores or autophagosomes to detach from the ER. Our work identifies a RAB GTPase-mediated autophagy process in plant cells, opening a door for improving crop productivity in the changing environment.
    Keywords:  ATG18; RABC1; TOR; autophagosomes; endoplasmic reticulum; nutrient starvation
    DOI:  https://doi.org/10.1080/15548627.2024.2314415
  8. J Cell Sci. 2024 Feb 01. pii: jcs260481. [Epub ahead of print]137(3):
    Driving autophagy - the role of molecular motors.
    Akshaya Nambiar, Ravi Manjithaya.
      Most of the vesicular transport pathways inside the cell are facilitated by molecular motors that move along cytoskeletal networks. Autophagy is a well-explored catabolic pathway that is initiated by the formation of an isolation membrane known as the phagophore, which expands to form a double-membraned structure that captures its cargo and eventually moves towards the lysosomes for fusion. Molecular motors and cytoskeletal elements have been suggested to participate at different stages of the process as the autophagic vesicles move along cytoskeletal tracks. Dynein and kinesins govern autophagosome trafficking on microtubules through the sequential recruitment of their effector proteins, post-translational modifications and interactions with LC3-interacting regions (LIRs). In contrast, myosins are actin-based motors that participate in various stages of the autophagic flux, as well as in selective autophagy pathways. However, several outstanding questions remain with regard to how the dominance of a particular motor protein over another is controlled, and to the molecular mechanisms that underlie specific disease variants in motor proteins. In this Review, we aim to provide an overview of the role of molecular motors in autophagic flux, as well as highlight their dysregulation in diseases, such as neurodegenerative disorders and pathogenic infections, and ageing.
    Keywords:  Adaptor proteins; Autophagy; Cytoskeleton; Dynein; Kinesin; Myosin
    DOI:  https://doi.org/10.1242/jcs.260481
  9. J Mol Biol. 2024 Feb 02. pii: S0022-2836(24)00044-5. [Epub ahead of print] 168472
    Physiological functions of ULK1/2.
    Gautam Pareek, Mondira Kundu.
      UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine kinases that are best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing the nutrient status of a cell, ULK1/2 integrate signals from upstream cellular energy sensors such as mTOR and AMPK and relay them to the downstream components of the autophagy machinery. ULK1/2 also play indispensable roles in the selective autophagy pathway, removing damaged mitochondria, invading pathogens, and toxic protein aggregates. Additional functions of ULK1/2 have emerged beyond autophagy, including roles in protein trafficking, RNP granule dynamics, and signaling events impacting innate immunity, axon guidance, cellular homeostasis, and cell fate. Therefore, it is no surprise that alterations in ULK1/2 expression and activity have been linked with pathophysiological processes, including cancer, neurological disorders, and cardiovascular diseases. Growing evidence suggests that ULK1/2 function as biological rheostats, tuning cellular functions to intra and extra-cellular cues. Given their broad physiological relevance, ULK1/2 are candidate targets for small molecule activators or inhibitors that may pave the way for the development of therapeutics for the treatment of diseases in humans.
    Keywords:  Aggrephagy; Autophagy; Biomolecular condensates; Interferon response; Mitophagy
    DOI:  https://doi.org/10.1016/j.jmb.2024.168472
  10. Amino Acids. 2024 Feb 04. 56(1): 7
    The dual role of autophagy in the regulation of cancer treatment.
    Louis Boafo Kwantwi.
      As a catabolic process, autophagy through lysosomes degrades defective and damaged cellular materials to support homeostasis in stressful conditions. Therefore, autophagy dysregulation is associated with the induction of several human pathologies, including cancer. Although the role of autophagy in cancer progression has been extensively studied, many issues need to be addressed. The available evidence suggest that autophagy shows both cytoprotective and cytotoxic mechanisms. This dual role of autophagy in cancer has supplied a renewed interest in the development of novel and effective cancer therapies. Considering this, a deeper understanding of the molecular mechanisms of autophagy in cancer treatment is crucial. This article provides a summary of the recent advances regarding the dual and different mechanisms of autophagy-mediated therapeutic efficacy in cancer.
    Keywords:  Autophagy; Drug resistance; The dual role; Therapeutic efficacy
    DOI:  https://doi.org/10.1007/s00726-023-03364-4
  11. Stem Cell Reports. 2024 Jan 20. pii: S2213-6711(24)00005-5. [Epub ahead of print]
    ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.
    Jacob A Klickstein, Michelle A Johnson, Pantelis Antonoudiou, Jamie Maguire, Joao A Paulo, Steve P Gygi, Chris Weihl, Malavika Raman.
      Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to clear damaged lysosomes and have reduced viability. Lysosomes in mutant motor neurons have increased pH compared with wild-type cells. The clearance of damaged lysosomes involves UBXD1-p97 interaction, which is disrupted in mutant motor neurons. Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.
    Keywords:  ALS; autophagy; galectin; lysophagy; lysosome; mitochondria; p97; proteomics
    DOI:  https://doi.org/10.1016/j.stemcr.2024.01.002
  12. Cell Mol Gastroenterol Hepatol. 2024 Feb 07. pii: S2352-345X(24)00034-1. [Epub ahead of print]
    Multiple genes core to ERAD, macro-autophagy and lysosomal degradation pathways participate in the proteostasis response in α1-antitrypsin deficiency.
    Jie Li, Francesca Moretti, Tunda Hidvegi, Sanja Sviben, James Aj Fitzpatrick, Hemalatha Sundaramoorthi, Stephen C Pak, Gary A Silverman, Britta Knapp, Ireos Filipuzzi, John Alford, John Reece-Hoyes, Florian Nigsch, Leon O Murphy, Beat Nyfeler, David H Perlmutter.
       BACKGROUND: In the classical form of α1-antitrypsin deficiency (ATD), the misfolded α1-antitrypsin Z (ATZ) variant accumulates in the endoplasmic reticulum (ER) of liver cells. A gain-of-function proteotoxic mechanism is responsible for chronic liver disease in a sub-group of homozygotes. Proteostatic response pathways, including conventional ERAD and autophagy, have been proposed as the mechanisms that allow cellular adaptation and presumably protection from the liver disease phenotype. Recent studies have concluded that a distinct lysosomal pathway called ERLAD completely supplants the role of the conventional macro-autophagy pathway in degradation of ATZ. Here we used several state-of-the-art approaches to more fully characterize the proteostatic responses in cellular systems that model ATD.
    METHODS: We used CRISPR-mediated genome editing coupled to a cell selection step by FACS to carry out screening for proteostasis genes that regulate ATZ accumulation and combined that with selective genome editing in two other model systems.
    RESULTS: ERAD genes are key early regulators and multiple autophagy genes, from classical as well as from ERLAD and other newly described ER-phagy pathways, participate in degradation of ATZ in a manner that is temporally regulated and evolves as ATZ accumulation persists. Time-dependent changes in gene expression are accompanied by specific ultrastructural changes including dilation of the ER, formation of globular inclusions, budding of autophagic vesicles and alterations in the overall shape and component parts of mitochondria.
    CONCLUSIONS: Macro-autophagy is a critical component of the proteostasis response to cellular ATZ accumulation and it becomes more important over time as ATZ synthesis continues unabated. Multiple sub-types of macro-autophagy and non-autophagic lysosomal degradative pathways are needed to respond to the high concentrations of misfolded protein that characterizes ATD and these pathways are attractive candidates for genetic variants that predispose to the hepatic phenotype.
    Keywords:  Autophagy; aggregation-prone proteins; liver disease; proteasome; α1-antitrypsin deficiency
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.02.006
  13. Semin Cancer Biol. 2024 Feb 01. pii: S1044-579X(24)00009-9. [Epub ahead of print]
    The Obesity-Autophagy-Cancer Axis: Mechanistic Insights and Therapeutic Perspectives.
    Amir Barzegar Behrooz, Marco Cordani, Alessandra Fiore, Massimo Donadelli, Joseph W Gordon, Daniel J Klionsky, Saeid Ghavami.
      Autophagy, a self-degradative process vital for cellular homeostasis, plays a significant role in adipose tissue metabolism and tumorigenesis. This review aims to elucidate the complex interplay between autophagy, obesity, and cancer development, with a specific emphasis on how obesity-driven changes affect the regulation of autophagy and subsequent implications for cancer risk. The burgeoning epidemic of obesity underscores the relevance of this research, particularly given the established links between obesity, autophagy, and various cancers. Our exploration delves into hormonal influence, notably insulin and LEP (leptin), on obesity and autophagy interactions. Further, we draw attention to the latest findings on molecular factors linking obesity to cancer, including hormonal changes, altered metabolism, and secretory autophagy. We posit that targeting autophagy modulation may offer a potent therapeutic approach for obesity-associated cancer, pointing to promising advancements in nanocarrier-based targeted therapies for autophagy modulation. However, we also recognize the challenges inherent to these approaches, particularly concerning their precision, control, and the dual roles autophagy can play in cancer. Future research directions include identifying novel biomarkers, refining targeted therapies, and harmonizing these approaches with precision medicine principles, thereby contributing to a more personalized, effective treatment paradigm for obesity-mediated cancer.
    Keywords:  Autophagy; Cancer; Nanocarrier; Obesity; Targeted Therapies
    DOI:  https://doi.org/10.1016/j.semcancer.2024.01.003
  14. Int J Mol Sci. 2024 Jan 26. pii: 1561. [Epub ahead of print]25(3):
    Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer.
    Xueni Yang, Shizheng Xiong, Xinmiao Zhao, Jiaming Jin, Xinbing Yang, Yajing Du, Linjie Zhao, Zhiheng He, Chengjun Gong, Li Guo, Tingming Liang.
      Autophagy, a complex and highly regulated cellular process, is critical for the maintenance of cellular homeostasis by lysosomal degradation of cellular debris, intracellular pathogens, and dysfunctional organelles. It has become an interesting and attractive topic in cancer because of its dual role as a tumor suppressor and cell survival mechanism. As a highly conserved pathway, autophagy is strictly regulated by diverse non-coding RNAs (ncRNAs), ranging from short and flexible miRNAs to lncRNAs and even circRNAs, which largely contribute to autophagy regulatory networks via complex RNA interactions. The potential roles of RNA interactions during autophagy, especially in cancer procession and further anticancer treatment, will aid our understanding of related RNAs in autophagy in tumorigenesis and cancer treatment. Herein, we mainly summarized autophagy-related mRNAs and ncRNAs, also providing RNA-RNA interactions and their potential roles in cancer prognosis, which may deepen our understanding of the relationships between various RNAs during autophagy and provide new insights into autophagy-related therapeutic strategies in personalized medicine.
    Keywords:  autophagy; cancer; circRNA; interaction; lncRNA; miRNA
    DOI:  https://doi.org/10.3390/ijms25031561
  15. bioRxiv. 2023 Oct 06. pii: 2023.10.06.560931. [Epub ahead of print]
    Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling.
    Yen-Ching Chang, Yuan Gao, Joo Yeun Lee, Jennifer Langen, Karen T Chang.
      The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity from synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We further demonstrate that neuronal activity stimulates autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a novel trans-synaptic signaling mechanism modulating structural plasticity.
    DOI:  https://doi.org/10.1101/2023.10.06.560931
  16. Cell Death Differ. 2024 Feb 08.
    DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins.
    Fei Jia, Xiaoman Wang, Yuhua Fu, Shi-Min Zhao, Boxun Lu, Chenji Wang.
      Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. One subtype of HSP, known as SPG54, is caused by biallelic mutations in the DDHD2 gene. The primary pathological feature observed in patients with SPG54 is the massive accumulation of lipid droplets (LDs) in the brain. However, the precise mechanisms and roles of DDHD2 in regulating lipid homeostasis are not yet fully understood. Through Affinity Purification-Mass Spectroscopy (AP-MS) analysis, we identify that DDHD2 interacts with multiple members of the ATG8 family proteins (LC3, GABARAPs), which play crucial roles in lipophagy. Mutational analysis reveals the presence of two authentic LIR motifs in DDHD2 protein that are essential for its binding to LC3/GABARAPs. We show that DDHD2 deficiency leads to LD accumulation, while enhanced DDHD2 expression reduces LD formation. The LC3/GABARAP-binding capacity of DDHD2 and the canonical autophagy pathway both contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a small molecule that tethers LC3 to LDs to enhance their autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide valuable insights into the regulatory roles of DDHD2 in LD catabolism and offer a potential therapeutic approach for treating SPG54 patients.
    DOI:  https://doi.org/10.1038/s41418-024-01261-1
  17. Sci Adv. 2024 Feb 09. 10(6): eadi2671
    Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation.
    Jaakko Mattila, Arto Viitanen, Gaia Fabris, Tetiana Strutynska, Jerome Korzelius, Ville Hietakangas.
      The adult intestine is a regionalized organ, whose size and cellular composition are adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear. Here, we show that intestinal nutrient adaptation involves region-specific control of cell size, cell number, and differentiation. We uncovered that activation of mTOR complex 1 (mTORC1) increases ISC size in a region-specific manner. mTORC1 activity promotes Delta expression to direct cell fate toward the absorptive enteroblast lineage while inhibiting secretory enteroendocrine cell differentiation. In aged flies, the ISC mTORC1 signaling is deregulated, being constitutively high and unresponsive to diet, which can be mitigated through lifelong intermittent fasting. In conclusion, mTORC1 signaling contributes to the ISC fate decision, enabling regional control of intestinal cell differentiation in response to nutrition.
    DOI:  https://doi.org/10.1126/sciadv.adi2671
  18. J Cell Biol. 2024 Mar 04. pii: e202306040. [Epub ahead of print]223(3):
    Rab32 family proteins regulate autophagosomal components recycling.
    Zhe Wu, Huilin Que, Chuangpeng Li, Li Yan, Shixuan Wang, Yueguang Rong.
      In autophagy, autophagosomes deliver the lumenal contents to lysosomes for degradation via autophagosome-lysosome fusion. In contrast, autophagosome outer membrane components were recycled via autophagosomal components recycling (ACR), which is mediated by the recycler complex. The recycler complex, composed of SNX4, SNX5, and SNX17, cooperate with the dynein-dynactin complex to mediate ACR. However, how ACR is regulated remains unknown. Here, we found that Rab32 family proteins localize to autolysosomes and are required for ACR, rather than other autophagosomal or lysosomal Rab proteins. The GTPase activity of Rab32 family proteins, governed by their guanine nucleotide exchange factor and GTPase-activating protein, plays a key role in regulating ACR. This regulation occurs through the control of recycler complex formation, as well as the connection between the recycler-cargo and dynactin complex. Together, our study reveals an unidentified Rab32 family-dependent regulatory mechanism for ACR.
    DOI:  https://doi.org/10.1083/jcb.202306040
  19. Breast Cancer. 2024 Feb 05.
    Advances in the study of autophagy in breast cancer.
    Tang Yu, Liu Rui, Zhao Jiumei, Li Ziwei, Hu Ying.
      Breast cancer is the most prevalent malignant tumor among women, with a high incidence and mortality rate all year round, which seriously affects women's health. Autophagy, a well-conserved cellular process inherent in eukaryotic organisms, plays a pivotal role in degrading damaged proteins and organelles, recycling their breakdown products to aid cells in navigating stress and gradually restoring homeostatic equilibrium. Recent studies have unveiled the intricate connection between autophagy and breast cancer. Autophagy is a double-edged sword in breast cancer, demonstrating a dual role: restraining its onset and progression on one hand, while promoting its metastasis and advancement on the other. It is also because of this interrelationship between the two that regulation of autophagy in the treatment of breast cancer is now an important strategy in clinical treatment. In this article, we systematically survey the recent research findings, elucidating the multifaceted role of autophagy in breast cancer and its underlying mechanisms, with the aim of contributing new references to the clinical management of breast cancer.
    Keywords:  Autophagy; Autophagy inhibitor; Breast cancer; Molecular mechanism; Therapy
    DOI:  https://doi.org/10.1007/s12282-023-01541-7
  20. FEBS Lett. 2024 Feb 04.
    Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
    Aksel J Saukko-Paavola, Robin W Klemm.
      Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.
    Keywords:  autophagy; endoplasmic reticulum (ER); lipid droplets (LDs); membrane contact sites; metabolic adaptation; mitochondria; mitochondrial shape; organelle-network; starvation
    DOI:  https://doi.org/10.1002/1873-3468.14813
  21. Neuron. 2024 Feb 07. pii: S0896-6273(24)00037-0. [Epub ahead of print]112(3): 520
    Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
    Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.
      
    DOI:  https://doi.org/10.1016/j.neuron.2024.01.011
  22. J Infect Dis. 2024 Feb 08. pii: jiae063. [Epub ahead of print]
    Uropathogenic Escherichia coli subverts host autophagic defenses by stalling pre-autophagosomal structures to escape lysosome exocytosis.
    Xueping Li, Lingyan Jiang, Si Zhang, Jiarui Zhou, Le Liu, Chen Jin, Hongmin Sun, Qian Wang, Yutao Liu, Yu Pang.
      Urinary tract infections are primarily caused by uropathogenic Escherichia coli (UPEC). UPEC infects bladder epithelial cells (BECs) via fusiform vesicles and escapes into the cytosol by disrupting fusiform vesicle membrane using outer membrane phospholipase PldA, and establishes biofilm-like intracellular bacterial communities (IBCs) for protection from host immune clearance. Cytosolic UPEC is captured by autophagy to form autophagosomes, then transport to lysosomes, triggering the spontaneous exocytosis of lysosomes. The mechanism by which UPEC evades autophagy to recognize and form IBCs remains unclear. Here, we demonstrate that by inhibiting autophagic flux, UPEC PldA reduces the lysosome exocytosis of BECs. By reducing intracellular PI3P levels, UPEC PldA increases the accumulation of NDP52 granules and decreases the targeting of NDP52 to autophagy, hence stalling pre-autophagosome structures. Thus, our results uncover a critical role for PldA to inhibit autophagic flux, favoring UPEC escapes from lysosome exocytosis, thereby contributing to acute UTI.
    Keywords:  PldA; autophagic flux; lysosome exocytosis; uropathogenic Escherichia coli
    DOI:  https://doi.org/10.1093/infdis/jiae063
  23. PNAS Nexus. 2024 Feb;3(2): pgae018
    p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury.
    Eda Karakaya, Natalia Oleinik, Jazlyn Edwards, Jensen Tomberlin, Randy Bent Barker, Burak Berber, Maria Ericsson, Habeeb Alsudani, Adviye Ergul, Semir Beyaz, John J Lemasters, Besim Ogretmen, Onder Albayram.
      Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide-induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.
    DOI:  https://doi.org/10.1093/pnasnexus/pgae018
  24. Sci Adv. 2024 Feb 09. 10(6): eadj8027
    Three-step docking by WIPI2, ATG16L1, and ATG3 delivers LC3 to the phagophore.
    Shanlin Rao, Marvin Skulsuppaisarn, Lisa M Strong, Xuefeng Ren, Michael Lazarou, James H Hurley, Gerhard Hummer.
      The covalent attachment of ubiquitin-like LC3 proteins (microtubule-associated proteins 1A/1B light chain 3) prepares the autophagic membrane for cargo recruitment. We resolve key steps in LC3 lipidation by combining molecular dynamics simulations and experiments in vitro and in cellulo. We show how the E3-like ligaseautophagy-related 12 (ATG12)-ATG5-ATG16L1 in complex with the E2-like conjugase ATG3 docks LC3 onto the membrane in three steps by (i) the phosphatidylinositol 3-phosphate effector protein WD repeat domain phosphoinositide-interacting protein 2 (WIPI2), (ii) helix α2 of ATG16L1, and (iii) a membrane-interacting surface of ATG3. Phosphatidylethanolamine (PE) lipids concentrate in a region around the thioester bond between ATG3 and LC3, highlighting residues with a possible role in the catalytic transfer of LC3 to PE, including two conserved histidines. In a near-complete pathway from the initial membrane recruitment to the LC3 lipidation reaction, the three-step targeting of the ATG12-ATG5-ATG16L1 machinery establishes a high level of regulatory control.
    DOI:  https://doi.org/10.1126/sciadv.adj8027
  25. STAR Protoc. 2024 Feb 05. pii: S2666-1667(24)00037-6. [Epub ahead of print]5(1): 102872
    Characterization of ATG8-family protein phosphorylation by Phos-tag gel for autophagy study.
    Gayoung Seo, Wenqi Wang.
      Autophagy supports cell survival under different stress conditions, where ATG8-family proteins are required for autophagosome biogenesis/maturation and selective autophagy. Here, we present a protocol for studying ATG8-family protein phosphorylation using Phos-tag gel, a modified SDS-PAGE system, when the related phosphorylation site information and/or specific phospho-antibody are unavailable. We describe steps for generating GST-ATG8 proteins in bacteria, purifying S protein-Flag-SBP protein (SFB)-tagged kinasefrom cells, preparing gel, and an in vitro kinase assay. We then detail procedures for western blotting and image processing. For complete details on the use and execution of this protocol, please refer to Seo et al.1.
    Keywords:  Protein Biochemistry; Protein expression and purification; Signal Transduction
    DOI:  https://doi.org/10.1016/j.xpro.2024.102872
  26. JCI Insight. 2024 Feb 08. pii: e169594. [Epub ahead of print]9(3):
    Inhibition of cysteine protease cathepsin Lincreases the level and activity of lysosomal glucocerebrosidase.
    Myung Jong Kim, Soojin Kim, Thomas Reinheckel, Dimitri Krainc.
      The glucocerebrosidase (GCase) encoded by the GBA1 gene hydrolyzes glucosylceramide (GluCer) to ceramide and glucose in lysosomes. Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disease Gaucher disease (GD) due to severe loss of GCase activity. Loss-of-function variants in the GBA1 gene are also the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Restoring lysosomal GCase activity represents an important therapeutic approach for GBA1-associated diseases. We hypothesized that increasing the stability of lysosomal GCase protein could correct deficient GCase activity in these conditions. However, it remains unknown how GCase stability is regulated in the lysosome. We found that cathepsin L, a lysosomal cysteine protease, cleaves GCase and regulates its stability. In support of these data, GCase protein was elevated in the brain of cathepsin L-KO mice. Chemical inhibition of cathepsin L increased both GCase levels and activity in fibroblasts from patients with GD. Importantly, inhibition of cathepsin L in dopaminergic neurons from a patient GBA1-PD led to increased GCase levels and activity as well as reduced phosphorylated α-synuclein. These results suggest that targeting cathepsin L-mediated GCase degradation represents a potential therapeutic strategy for GCase deficiency in PD and related disorders that exhibit decreased GCase activity.
    Keywords:  Cell Biology; Lysosomes; Neuroscience; Parkinson disease
    DOI:  https://doi.org/10.1172/jci.insight.169594
  27. Physiol Rep. 2024 Feb;12(3): e15928
    Tissue-specific expression differences in Ras-related GTP-binding proteins in male rats.
    Gregory N Kincheloe, Paul A Roberson, Leonard S Jefferson, Scot R Kimball.
      The protein kinase Mechanistic Target of Rapamycin (mTOR) in Complex 1 (mTORC1) is regulated in part by the Ras-related GTP-binding proteins (Rag GTPases). Rag GTPases form a heterodimeric complex consisting of either RagA or RagB associated with either RagC or RagD and act to localize mTORC1 to the lysosomal membrane. Until recently, RagA and RagB were thought to be functionally redundant, as were RagC and RagD. However, recent research suggests that the various isoforms differentially activate mTORC1. Here, the mRNA expression and protein abundance of the Rag GTPases was compared across male rat skeletal muscle, heart, liver, kidney, and brain. Whereas mRNA expression of RagA was higher than RagB in nearly all tissues studied, RagB protein abundance was higher than RagA in all tissues besides skeletal muscle. RagC mRNA expression was more abundant or equal to RagD mRNA, and RagD protein was more abundant than RagC protein in all tissues. Moreover, the proportion of RagB in the short isoform was greater than the long in liver, whereas the opposite was true in brain. These results serve to further elucidate Rag GTPase expression and offer potential explanations for the differential responses to amino acids that are observed in different tissues.
    Keywords:  Rag GTPases; RagB isoform; Ras-related GTP-binding proteins; amino acid signaling; mechanistic target of rapamycin in complex 1
    DOI:  https://doi.org/10.14814/phy2.15928
  28. Sci Adv. 2024 Feb 09. 10(6): eadj2752
    AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
    Liwei Xiao, Yujing Yin, Zongchao Sun, Jing Liu, Yuhuan Jia, Likun Yang, Yan Mao, Shujun Peng, Zhifu Xie, Lei Fang, Jingya Li, Xiaoduo Xie, Zhenji Gan.
      Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adj2752
  29. Sci Rep. 2024 Feb 08. 14(1): 3200
    The Ykt6-Snap29-Syx13 SNARE complex promotes crinophagy via secretory granule fusion with Lamp1 carrier vesicles.
    Győző Szenci, Gábor Glatz, Szabolcs Takáts, Gábor Juhász.
      In the Drosophila larval salivary gland, developmentally programmed fusions between lysosomes and secretory granules (SGs) and their subsequent acidification promote the maturation of SGs that are secreted shortly before puparium formation. Subsequently, ongoing fusions between non-secreted SGs and lysosomes give rise to degradative crinosomes, where the superfluous secretory material is degraded. Lysosomal fusions control both the quality and quantity of SGs, however, its molecular mechanism is incompletely characterized. Here we identify the R-SNARE Ykt6 as a novel regulator of crinosome formation, but not the acidification of maturing SGs. We show that Ykt6 localizes to Lamp1+ carrier vesicles, and forms a SNARE complex with Syntaxin 13 and Snap29 to mediate fusion with SGs. These Lamp1 carriers represent a distinct vesicle population that are functionally different from canonical Arl8+, Cathepsin L+ lysosomes, which also fuse with maturing SGs but are controlled by another SNARE complex composed of Syntaxin 13, Snap29 and Vamp7. Ykt6- and Vamp7-mediated vesicle fusions also determine the fate of SGs, as loss of either of these SNAREs prevents crinosomes from acquiring endosomal PI3P. Our results highlight that fusion events between SGs and different lysosome-related vesicle populations are critical for fine regulation of the maturation and crinophagic degradation of SGs.
    DOI:  https://doi.org/10.1038/s41598-024-53607-x
  30. Nat Commun. 2024 Feb 03. 15(1): 1021
    Phosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome.
    Shao-Ling Chu, Jia-Rong Huang, Yu-Tzu Chang, Shu-Yun Yao, Jia-Shu Yang, Victor W Hsu, Jia-Wei Hsu.
      The epidermal growth factor receptor (EGFR) plays important roles in multiple cellular events, including growth, differentiation, and motility. A major mechanism of downregulating EGFR function involves its endocytic transport to the lysosome. Sorting of proteins into intracellular pathways involves cargo adaptors recognizing sorting signals on cargo proteins. A dileucine-based sorting signal has been identified previously for the sorting of endosomal EGFR to the lysosome, but a cargo adaptor that recognizes this signal remains unknown. Here, we find that phosphoglycerate kinase 1 (PGK1) is recruited to endosomal membrane upon its phosphorylation, where it binds to the dileucine sorting signal in EGFR to promote the lysosomal transport of this receptor. We also elucidate two mechanisms that act in concert to promote PGK1 recruitment to endosomal membrane, a lipid-based mechanism that involves phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and a protein-based mechanism that involves hepatocyte growth factor receptor substrate (Hrs). These findings reveal an unexpected function for a metabolic enzyme and advance the mechanistic understanding of how EGFR is transported to the lysosome.
    DOI:  https://doi.org/10.1038/s41467-024-45443-4
  31. iScience. 2024 Feb 16. 27(2): 108883
    Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.
    Yunfan He, Gao Zhu, Xincheng Li, Mi Zhou, Min-Xin Guan.
      Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we demonstrated that mt-tRNAMet 4435A>G mutation-induced nucleotide modification deficiency dysregulated the expression of nuclear genes involved in cytosolic proteins involved in oxidative phosphorylation system (OXPHOS) and impaired the assemble and integrity of OXPHOS complexes. These dysfunctions caused mitochondrial dynamic imbalance, thereby increasing fission and decreasing fusion. Excessive fission impaired the process of autophagy including initiation phase, formation, and maturation of autophagosome. Strikingly, the m.4435A>G mutation upregulated the PARKIN dependent mitophagy pathways but downregulated the ubiquitination-independent mitophagy. These alterations promoted intrinsic apoptotic process for the removal of damaged cells. Our findings provide new insights into mechanism underlying deficient tRNA posttranscription modification regulated intracellular signaling related to the mitochondrial and cellular integrity.
    Keywords:  Cell biology; Molecular physiology; Properties of biomolecules
    DOI:  https://doi.org/10.1016/j.isci.2024.108883
  32. Free Radic Biol Med. 2024 Feb 06. pii: S0891-5849(24)00065-0. [Epub ahead of print]
    Sestrin2 reduces ferroptosis via the Keap1/Nrf2 signaling pathway after intestinal ischemia-reperfusion.
    Le-le Zhang, Ke Ding, Shi-Shi Liao, Yi-Guo Zhang, Hui-Yang Liao, Rong Chen, Qing-Tao Meng.
      Sestrins are metabolic regulators that respond to stress by reducing the levels of reactive oxygen species (ROS) and inhibiting the activity of target of rapamycin complex 1 (mTORC1). Previous research has demonstrated that Sestrin2 mitigates ischemia-reperfusion (IR) injury in the heart, liver, and kidneys. However, its specific role in IIR injury remains unclear. To elucidate the role of Sestrin2 in intestinal ischemia-reperfusion injury, we conducted an experimental study using a C57BL/6J mouse model of IIR. We noticed an increase in the levels of Sestrin2 expression and indicators associated with ferroptosis. Our study revealed that manipulating Sestrin2 expression in Caco-2 cells through overexpression or knockdown resulted in a corresponding decrease or increase, respectively, in ferroptosis levels. Furthermore, our investigation revealed that Sestrin2 alleviated ferroptosis caused by IIR injury through the activation of the Keap1/Nrf2 signaling pathway. This finding highlights the potential of Sestrin2 as a therapeutic target for alleviating IIR injury. These findings indicated that the modulation of Sestrin2 could be a promising strategy for managing prolonged IIR injury.
    Keywords:  Ferroptosis; Intestinal ischemia-reperfusion; Keap1; Nrf2; Sestrin2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.02.003
  33. bioRxiv. 2024 Jan 25. pii: 2024.01.24.576953. [Epub ahead of print]
    PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
    Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Merima Forny, Jonathan R Friedman, Natalie M Niemi.
      PPTC7 is a mitochondrial-localized PP2C phosphatase that maintains mitochondrial protein content and metabolic homeostasis. We previously demonstrated that knockout of Pptc7 elevates mitophagy in a BNIP3- and NIX-dependent manner, but the mechanisms by which PPTC7 influences receptor-mediated mitophagy remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. On a molecular level, loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels in response to pseudohypoxia, a well-known inducer of mitophagy. This PPTC7-mediated suppression of BNIP3 and NIX protein expression requires an intact PP2C catalytic motif but is surprisingly independent of its mitochondrial targeting, indicating that PPTC7 influences mitophagy outside of the mitochondrial matrix. We find that PPTC7 exists in at least two distinct states in cells: a longer isoform, which likely represents full length protein, and a shorter isoform, which likely represents an imported, matrix-localized phosphatase pool. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments suggest that PPTC7 associates with BNIP3 and NIX within the native cellular environment. Importantly, these associations are enhanced in cellular conditions that promote BNIP3 and NIX turnover, demonstrating that PPTC7 is dynamically recruited to BNIP3 and NIX to facilitate their degradation. Collectively, these data reveal that a fraction of PPTC7 dynamically localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX.
    DOI:  https://doi.org/10.1101/2024.01.24.576953
  34. Front Pharmacol. 2023 ;14 1291195
    A global bibliometric and visualized analysis of the links between the autophagy and acute myeloid leukemia.
    Yao Gao, Zhenhui Wu, Yingfan Chen, Guangbin Shang, Yingjian Zeng, Yue Gao.
      Background and objectives: Autophagy is a cellular process where damaged organelles or unwanted proteins are packaged into a double-membrane structure and transported to lysosomes for degradation. Autophagy plays a regulatory role in various hematologic malignancies, including acute myeloid leukemia (AML). However, there are few bibliometric studies on the role of autophagy in AML. The purpose of this study is to clarify the role of autophagy in acute myeloid leukemia through bibliometric analysis. Methods: The literature on autophagy and AML research from 2003 to 2023 was searched in Web of Science Core Collection, and bibliometric tools such as VOSviewer 1.6.18, Cite Space (6.1.R3), RStudio (R package bibliometrix), and Scimago Graphica were used to understand the current status and hotspots of autophagy and AML research. The study conducted an analysis of various dimensions including the quantity of publications, countries, institutions, journals, authors, co-references, keywords, and to predict future development trends in this field by drawing relevant visualization maps. Results: A total of 343 articles were obtained, published in 169 journals, written by 2,323 authors from 295 institutions in 43 countries. The journals with the most publications were Blood and Oncotarget. China had the most publications, and Chongqing Medical University and Sun Yat-sen University had the most publications. The author with the highest number of publications was Tschan, Mario P. The main types of research included clinical research, in vitro experiments, in vivo experiments, public database information, and reviews, and the forms of therapeutic effects mainly focused on genetic regulation, traditional Chinese medicine combination, autophagy inhibitors, and drug targets. The research hotspots of autophagy and AML in the past 17 years have focused on genetic regulation, autophagy inhibition, and targeted drugs. Chemotherapy resistance and mitochondrial autophagy will be the forefront of research. Conclusion: The gradual increase in the literature on autophagy and AML research and the decline after 2022 could be a result of authors focusing more on the type of research and the quality of the literature. The current research hotspots are mainly genetic regulation, autophagy inhibition, and autophagy-related targeted drugs. In future, autophagy will remain the focus of the AML field, with research trends likely to focus more on AML chemotherapy resistance and mitochondrial autophagy.
    Keywords:  acute myeloid leukemia; autophagy; bibliometric analysis; chemotherapy resistance; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2023.1291195
  35. Biochim Biophys Acta Mol Basis Dis. 2024 Feb 05. pii: S0925-4439(24)00028-0. [Epub ahead of print]1870(4): 167043
    MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.
    Haolin Duan, Cunhui Pan, Tenghui Wu, Jing Peng, Li Yang.
      Mitochondrial encephalopathy is a neurological disorder caused by impaired mitochondrial function and energy production. One of the genetic causes of this condition is the mutation of MT-TN, a gene that encodes the mitochondrial transfer RNA (tRNA) for asparagine. MT-TN mutations affect the stability and structure of the tRNA, resulting in reduced protein synthesis and complex enzymatic deficiency of the mitochondrial respiratory chain. Our patient cohort manifests with epileptic encephalopathy, ataxia, hypotonia, and bilateral basal ganglia calcification, which differs from previously reported cases. MT-TN mutation deficiency leads to decreased basal and maximal oxygen consumption rates, disrupted spare respiratory capacity, declined mitochondrial membrane potential, and impaired ATP production. Moreover, MT-TN mutations promote mitophagy, a process of selective degradation of damaged mitochondria by autophagy. Excessive mitophagy further leads to mitochondrial biogensis as a compensatory mechanism. In this study, we provided evidence of pathogenicity for two MT-TN mutations, m.5688 T > C and m.G5691A, explored the molecular mechanisms, and summarized the clinical manifestations of MT-TN mutations. Our study expanded the genotype and phenotypic spectrum and provided new insight into mt-tRNA (Asn)-associated mitochondrial encephalopathy.
    Keywords:  Epilepsy; MT-TN; Mitochondrial encephalopathy; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167043
  36. Cell Mol Life Sci. 2024 Feb 05. 81(1): 75
    LRP10 and α-synuclein transmission in Lewy body diseases.
    Ana Carreras Mascaro, Martyna M Grochowska, Valerie Boumeester, Natasja F J Dits, Ece Naz Bilgiҫ, Guido J Breedveld, Leonie Vergouw, Frank Jan de Jong, Martin E van Royen, Vincenzo Bonifati, Wim Mandemakers.
      Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.
    Keywords:  Astrocytes; Brain organoids; Dementia with Lewy bodies (DLB); Extracellular vesicles (EVs); Induced pluripotent stem cells (iPSC); Lewy body diseases (LBDs); Low-density lipoprotein receptor-related protein 10 (LRP10); Parkinson’s disease (PD); α-Synuclein
    DOI:  https://doi.org/10.1007/s00018-024-05135-0
  37. J Biol Chem. 2024 Feb 01. pii: S0021-9258(24)00080-2. [Epub ahead of print] 105704
    KAT8 is upregulated and recruited to the promoter of Atg8 by FOXO to induce H4 acetylation for autophagy under 20-hydroxyecdysone regulation.
    Tian-Wen Liu, Yu-Meng Zhao, Ke-Yan Jin, Jin-Xing Wang, Xiao-Fan Zhao.
      Selective gene expression in cells in physiological or pathological conditions is important for the growth and development of organisms. Acetylation of K16 (H4K16ac) catalyzed by histone acetyltransferase 8 (KAT8) is known to promote gene transcription; however, the regulation of KAT8 transcription and the mechanism by which KAT8 acetylates H4K16ac to promote specific gene expression are unclear. Here, using the lepidopteran insect Helicoverpa armigera as a model, we reveal that the transcription factor FOXO promotes KAT8 expression and recruits KAT8 to the promoter region of autophagy-related gene 8 (Atg8) to increase H4 acetylation at that location, enabling Atg8 transcription under the steroid hormone 20-hydroxyecdysone (20E) regulation. H4K16ac levels are increased in the midgut during metamorphosis, which is consistent with the expression profiles of KAT8 and ATG8. Knockdown of Kat8 using RNA interference results in delayed pupation and repression of midgut autophagy and decreases H4K16ac levels. Overexpression of KAT8-GFP promotes autophagy and increases H4K16ac levels. FOXO, KAT8 and H4K16ac colocalized at the FOXO binding region to promote Atg8 transcription under 20E regulation. Acetylated FOXO at K180 and K183 catalyzed by KAT8 promotes gene transcription for autophagy. 20E via FOXO promotes Kat8 transcription. Knockdown or overexpression of FOXO appeared to give similar results as knockdown or overexpression KAT8. Therefore, FOXO upregulates KAT8 expression and recruits KAT8 to the promoter region of Atg8, where the KAT8 induces H4 acetylation to promote Atg8 transcription for autophagy under 20E regulation. This study reveals the mechanism that KAT8 to promote transcription of a specific gene.
    Keywords:  20-hydroxyecdysone; FOXO; H4K16ac; KAT8; autophagy
    DOI:  https://doi.org/10.1016/j.jbc.2024.105704
  38. Metabolism. 2024 Feb 01. pii: S0026-0495(24)00037-4. [Epub ahead of print] 155811
    Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth.
    Zahra Dashti, Zeynab Yousefi, Pouria Kiani, Motahareh Taghizadeh, Mohammad Hasan Maleki, Mohammad Borji, Omid Vakili, Sayed Mohammad Shafiee.
      The incidence of nonalcoholic fatty liver disease (NAFLD) is on the rise, mirroring a global surge in diabetes and metabolic syndrome, as its major leading causes. NAFLD represents a spectrum of liver disorders, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Mechanistically, we know the unfolded protein response (UPR) as a protective cellular mechanism, being triggered under circumstances of endoplasmic reticulum (ER) stress. The hepatic UPR is turned on in a broad spectrum of liver diseases, including NAFLD. Recent data also defines molecular mechanisms that may underlie the existing correlation between UPR activation and NAFLD. More interestingly, subsequent studies have demonstrated an additional mechanism, i.e. autophagy, to be involved in hepatic steatosis, and thus NAFLD pathogenesis, principally by regulating the insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. All these findings suggest possible mechanistic roles for autophagy in the progression of NALD and its complications. Both UPR and autophagy are dynamic and interconnected fluxes that act as protective responses to minimize the harmful effects of hepatic lipid accumulation, as well as the ER stress during NAFLD. The functions of UPR and autophagy in the liver, together with findings of decreased hepatic autophagy in correlation with conditions that predispose to NAFLD, such as obesity and aging, suggest that autophagy and UPR, alone or combined, may be novel therapeutic targets against the disease. In this review, we discuss the current evidence on the interplay between autophagy and the UPR in connection to the NAFLD pathogenesis.
    Keywords:  Autophagy; Endoplasmic reticulum stress; Metabolism; Non-alcoholic fatty liver disease; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.metabol.2024.155811
  39. bioRxiv. 2024 Jan 25. pii: 2024.01.25.577235. [Epub ahead of print]
    Rbpms2 promotes female fate upstream of the nutrient sensing Gator2 complex component, Mios.
    Miranda L Wilson, Shannon N Romano, Nitya Khatri, Devora Aharon, Yulong Liu, Odelya H Kaufman, Bruce W Draper, Florence L Marlow.
      Reproductive success relies on proper establishment and maintenance of biological sex. In many animals, including mammals, the primary gonad is initially ovary in character. We previously showed the RNA binding protein (RNAbp), Rbpms2, is required for ovary fate in zebrafish. Here, we identified Rbpms2 targets in oocytes (Rbpms2-bound oocyte RNAs; rboRNAs ). We identify Rbpms2 as a translational regulator of rboRNAs , which include testis factors and ribosome biogenesis factors. Further, genetic analyses indicate that Rbpms2 promotes nucleolar amplification via the mTorc1 signaling pathway, specifically through the mTorc1-activating Gap activity towards Rags 2 (Gator2) component, Missing oocyte (Mios). Cumulatively, our findings indicate that early gonocytes are in a dual poised, bipotential state in which Rbpms2 acts as a binary fate-switch. Specifically, Rbpms2 represses testis factors and promotes oocyte factors to promote oocyte progression through an essential Gator2-mediated checkpoint, thereby integrating regulation of sexual differentiation factors and nutritional availability pathways in zebrafish oogenesis.
    DOI:  https://doi.org/10.1101/2024.01.25.577235
  40. Sci Transl Med. 2024 Feb 07. 16(733): eade8647
    DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition.
    Yuting Lu, Junyu Xu, Yufeng Li, Ruoran Wang, Chengqiu Dai, Bingqian Zhang, Xinwen Zhang, Lei Xu, Yunhua Tao, Ming Han, Ren Guo, Qingqian Wu, Linshi Wu, Zhuoxian Meng, Minjia Tan, Jingya Li.
      Impeded autophagy can impair pancreatic β cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic β cells protected β cell function against high-fat diet feeding along with sustained autophagy and mitochondrial function. Phosphoproteome analysis in isolated mouse primary islets revealed that DRAK2 directly phosphorylated unc-51-like autophagy activating kinase 1 (ULK1) at Ser56, which was subsequently found to induce ULK1 ubiquitylation and suppress autophagy. ULK1-S56A mutation or pharmacological inhibition of DRAK2 preserved mitochondrial function and insulin secretion against lipotoxicity in mouse primary islets, Min6 cells, or INS-1E cells. In conclusion, these findings together indicate an indispensable role of the DRAK2-ULK1 axis in pancreatic β cells upon metabolic challenge, which offers a potential target to protect β cell function in T2D.
    DOI:  https://doi.org/10.1126/scitranslmed.ade8647
  41. J Hazard Mater. 2024 Jan 28. pii: S0304-3894(24)00213-9. [Epub ahead of print]467 133634
    The role of mTORC1/TFEB axis mediated lysosomal biogenesis and autophagy impairment in fluoride neurotoxicity and the intervention effects of resveratrol.
    Huayang Tang, Haoqi Hou, Li Song, Zhiyuan Tian, Wenhui Liu, Tao Xia, Aiguo Wang.
      Elevated exposures to fluoride have been linked to neurological diseases. Identifying mechanisms of fluoride neurotoxicity and finding ways for prevention and treatment of epidemic fluorosis are important issues of public health. In this study, fluoride inhibited TFEB nuclear translocation by activating p-mTORC1/p-p70S6K, thus inhibiting lysosomal biogenesis, leading to dysfunctional lysosome accumulation, which further negatively affected autophagosome and lysosome fusion, thus impairing autophagy degradation, evidenced by the blocked conversion of LC3II to LC3I, and the increased p62 levels. Interestingly, RSV alleviated rats' cognition by improving fluoride-induced nerve damage and promoted lysosomal biogenesis demonstrated by the increased nucleus translocation of TFEB via inhibiting p-mTORC1 and p-p70S6K, the decreased expression of LC3II and p62. Collectively, we clarified the correlation between fluoride neurotoxicity and mTORC1/TFEB-mediated lysosomal biogenesis and autophagy. Meanwhile, RSV appeared to be a promising drug for the prevention and treatment of epidemic fluorosis.
    Keywords:  Fluoride; MTORC1; Neurotoxicity; Resveratrol; TFEB
    DOI:  https://doi.org/10.1016/j.jhazmat.2024.133634
  42. Cancer Lett. 2024 Feb 01. pii: S0304-3835(24)00056-9. [Epub ahead of print] 216662
    The interplay between autophagy and apoptosis: its implication in lung cancer and therapeutics.
    Urmita Biswas, Ranita Roy, Swarnasree Ghosh, Gopal Chakrabarti.
      Maintaining cellular homeostasis relies on the interplay between apoptosis and autophagy, and disruption in either of these processes can contribute to the development of cancer. Autophagy can hinder the apoptotic process, and when autophagy is inhibited in such instances, it can enhance the rate of apoptosis. However, evidence suggests that excessive autophagy can also lead to apoptotic cell death. Also, excess autophagy can cause excessive digestion of cellular organelles, causing autophagic cell death. Targeting autophagy in non-small cell lung cancer (NSCLC), the most common form of lung cancer, can be very tricky due to the dual nature of autophagy. According to genetic analysis, various mutations in p53 and EGFR, G:C to A:T transversions seem responsible for the development of lung cancer in smokers and non-smokers. These events trigger cytoprotective autophagy or induce apoptotic cell death through different but interconnected signalling pathways. Lung cancer being the leading cause of death worldwide, calls for more attention to disease prognosis and new therapeutics in the market. However, molecules responsible for autophagy to apoptosis transition are yet to be studied elaborately. Also, the role of effector caspases during this shift needs to be elucidated in future. To comprehend how therapeutics operate through the modulation of autophagy and apoptosis and to target such pathways, it is crucial to emphasize these intricate connections. Many therapeutics discussed in this review targeting both apoptosis and autophagy have shown promising results in vitro and in vivo, however, few have crossed the hurdles of clinical trial. Nevertheless, the quest for safer and better efficacious agents is still alive, with the sole aim to develop novel cancer chemotherapeutic(s).
    Keywords:  Apoptosis; Autophagy; Interplay; Non-small cell lung cancer (NSCLC); Therapeutics
    DOI:  https://doi.org/10.1016/j.canlet.2024.216662
  43. bioRxiv. 2024 Jan 23. pii: 2024.01.22.576497. [Epub ahead of print]
    WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.
    Alyssa M Coulter, Valerie Cortés, Corey J Theodore, Rachel E Cianciolo, Ron Korstanje, Kenneth G Campellone.
      The actin cytoskeleton is essential for many functions of eukaryotic cells, but the factors that nucleate actin assembly are not well understood at the organismal level or in the context of disease. To explore the function of the actin nucleation factor WHAMM in mice, we examined how Whamm inactivation impacts kidney physiology and cellular proteostasis. We show that male WHAMM knockout mice excrete elevated levels of albumin, glucose, phosphate, and amino acids, and display abnormalities of the kidney proximal tubule, suggesting that WHAMM activity is important for nutrient reabsorption. In kidney tissue, the loss of WHAMM results in the accumulation of the lipidated autophagosomal membrane protein LC3, indicating an alteration in autophagy. In mouse fibroblasts and human proximal tubule cells, WHAMM and its binding partner the Arp2/3 complex control autophagic membrane closure and cargo receptor recruitment. These results reveal a role for WHAMM-mediated actin assembly in maintaining kidney function and promoting proper autophagosome membrane remodeling.
    DOI:  https://doi.org/10.1101/2024.01.22.576497
  44. Int J Mol Sci. 2024 Jan 25. pii: 1489. [Epub ahead of print]25(3):
    Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.
    Mostafizur Rahman, Tuan Minh Nguyen, Gi Jeong Lee, Boram Kim, Mi Kyung Park, Chang Hoon Lee.
      Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1's involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.
    Keywords:  Rheb1; Rheb1 inhibitors; Rheb2; cancer; hallmarks; mTOR; neurons
    DOI:  https://doi.org/10.3390/ijms25031489
  45. FEBS J. 2024 Feb 05.
    PHGDH knockdown increases sensitivity to SR1, an aryl hydrocarbon receptor antagonist, in colorectal cancer by activating the autophagy pathway.
    Hong-Ming Li, Xiang Li, Ran Xia, Xing Zhang, Tong-Zhao Jin, Hong-Sheng Zhang.
      Colorectal cancer (CRC) has emerged as the third most prevalent and second deadliest cancer worldwide. Metabolic reprogramming is a key hallmark of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) is over-expressed in multiple cancers, including CRC. Although the role of PHGDH in metabolism has been extensively investigated, its effects on CRC development remains to be elucidated. In the present study, it was demonstrated that PHGDH expression was significantly up-regulated in colorectal cancer. PHGDH expression was positively correlated with that of the aryl hydrocarbon receptor (AhR) and its target genes, CYP1A1 and CYP1B1, in CRC cells. Knockdown of PHGDH reduced AhR levels and activity, as well as the ratio of reduced to oxidized glutathione. The selective AhR antagonist stemregenin 1 induced cell death through reactive oxygen species-dependent autophagy in CRC cells. PHGDH knockdown induced CRC cell sensitivity to stemregenin 1 via the autophagy pathway. Our findings suggest that PHGDH modulates AhR signaling and the redox-dependent autophagy pathway in CRC, and that the combination of inhibition of both PHGDH and AhR may be a novel therapeutic strategy for CRC.
    Keywords:  AhR; PHGDH; autophagy; colorectal cancer
    DOI:  https://doi.org/10.1111/febs.17080
  46. Biol Pharm Bull. 2024 ;47(1): 339-344
    Role of the Cytosolic Domain of the a3 Subunit of V-ATPase in the Interaction with Rab7 and Secretory Lysosome Trafficking in Osteoclasts.
    Mayumi Nakanishi-Matsui, Naomi Matsumoto, Ge-Hong Sun-Wada, Yoh Wada.
      We previously reported that the a3 subunit of proton-pumping vacuolar-type ATPase (V-ATPase) interacts with Rab7 and its guanine nucleotide exchange factor, Mon1a-Ccz1, and recruits them to secretory lysosomes in osteoclasts, which is essential for anterograde trafficking of secretory lysosomes. The a3 subunit interacts with Mon1a-Ccz1 through its cytosolic N-terminal domain. Here, we examined the roles of this domain in the interaction with Rab7 and trafficking of secretory lysosomes. Immunoprecipitation experiments showed that a3 interacted with Rab7 through its cytosolic domain, similar to the interaction with Mon1a-Ccz1. We connected this domain with a lysosome localization signal and expressed it in a3-knockout (a3KO) osteoclasts. Although the signal connected to the cytosolic domain was mainly detected in lysosomes, impaired lysosome trafficking in a3KO osteoclasts was not rescued. These results indicate that the cytosolic domain of a3 can interact with trafficking regulators, but is insufficient to induce secretory lysosome trafficking. The C-terminal domain of a3 and other subunits of V-ATPase are likely required to form a fully functional complex for secretory lysosome trafficking.
    Keywords:  Rab7; a3 isoform; osteoclast; secretory lysosome; vacuolar-type ATPase
    DOI:  https://doi.org/10.1248/bpb.b23-00833
  47. Oncotarget. 2024 Feb 08. 15 124-133
    GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.
    Michael R Booth, Laurence Booth, Jane L Roberts, Cameron West, Paul Dent.
      GZ17-6.02, composed of curcumin, harmine and isovanillin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not been studied. GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. All three components are necessary for optimal killing of MF cells. GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.
    Keywords:  ER stress; GZ17-6.02; autophagy; bexarotene; vorinostat
    DOI:  https://doi.org/10.18632/oncotarget.28557
  48. Cells. 2024 Jan 31. pii: 270. [Epub ahead of print]13(3):
    Evidence for Involvement of ADP-Ribosylation Factor 6 in Intracellular Trafficking and Release of Murine Leukemia Virus Gag.
    Hyokyun Kang, Taekwon Kang, Lauryn Jackson, Amaiya Murphy, Takayuki Nitta.
      Murine leukemia viruses (MuLVs) are simple retroviruses that cause several diseases in mice. Retroviruses encode three basic genes: gag, pol, and env. Gag is translated as a polyprotein and moves to assembly sites where viral particles are shaped by cleavage of poly-Gag. Viral release depends on the intracellular trafficking of viral proteins, which is determined by both viral and cellular factors. ADP-ribosylation factor 6 (Arf6) is a small GTPase that regulates vesicular trafficking and recycling of different types of cargo in cells. Arf6 also activates phospholipase D (PLD) and phosphatidylinositol-4-phosphate 5-kinase (PIP5K) and produces phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). We investigated how Arf6 affected MuLV release with a constitutively active form of Arf6, Arf6Q67L. Expression of Arf6Q67L impaired Gag release by accumulating Gag at PI(4,5)P2-enriched compartments in the cytoplasm. Treatment of the inhibitors for PLD and PIP5K impaired or recovered MuLV Gag release in the cells expressing GFP (control) and Arf6Q67L, implying that regulation of PI(4,5)P2 through PLD and PIP5K affected MuLV release. Interference with the phosphoinositide 3-kinases, mammalian target of rapamycin (mTOR) pathway, and vacuolar-type ATPase activities showed further impairment of Gag release from the cells expressing Arf6Q67L. In contrast, mTOR inhibition increased Gag release in the control cells. The proteasome inhibitors reduced viral release in the cells regardless of Arf6Q67L expression. These data outline the differences in MuLV release under the controlled and overactivated Arf6 conditions and provide new insight into pathways for MuLV release.
    Keywords:  ADP-ribosylation factor 6; PI(4,5)P2; autophagy; mammalian target of rapamycin; murine leukemia virus; phosphatidylinositol-4-phosphate 5-kinase; phosphoinositide 3-kinases; phospholipase D; proteasome inhibitors; vacuolar-type ATPase
    DOI:  https://doi.org/10.3390/cells13030270
  49. Ann Bot. 2024 Feb 07. pii: mcae015. [Epub ahead of print]
    Conserved autophagy and diverse cell wall composition: Unifying features of vascular tissues in evolutionarily distinct plants.
    Kornel M Michalak, Natalia Wojciechowska, Katarzyna Marzec-Schmidt, Agnieszka Bagniewska-Zadworna.
       BACKGROUND AND AIMS: The formation of multifunctional vascular tissues represents a significant advancement in plant evolution. Differentiation of conductive cells is specific, involving two main pathways - protoplast clearance and cell wall modification. In xylogenesis, autophagy is a crucial process of the complete protoplast elimination in tracheary elements, whose cell wall also undergoes strong changes.Knowledge pertaining to living sieve elements, which lose most of their protoplast during phloemogenesis, remains limited. We hypothesized that autophagy plays a critical role, not only in xylem complete cytoplasmic clearance but also in partial degradation in phloem. Cell wall elaborations of mature sieve elements are not so extensive. These analyses performed on evolutionary diverse model species potentially make it possible to understand phloemogenesis to an equal extent as xylogenesis.
    METHODS: We investigated the distribution of ATG8 protein, which is an autophagy marker, and cell wall components in the roots of ferns, gymnosperms, and angiosperms (monocots, dicot herbaceous plants, and trees). Furthermore, we conducted a bioinformatic analysis of complete data on ATG8 isoforms for Ceratopteris richardii.
    KEY RESULTS: The presence of ATG8 protein was confirmed in both tracheary elements and sieve elements; however, the composition of cell wall components varied considerably among vascular tissues in the selected plants. Arabinogalactan proteins and β-1,4-galactan were detected in the roots of all studied species, suggesting their potential importance in phloem formation or function. In contrast, no evolutionary pattern was observed for xyloglucan, arabinan, or homogalacturonan.
    CONCLUSIONS: Our study's findings indicate that the involvement of autophagy in plants is universal during the development of tracheary elements that are dead at maturity and sieve elements that remain alive. Given the conserved nature of autophagy, and its function in protoplast degradation for uninterrupted flow, autophagy may have played a vital role in the development of increasingly complex biological organizations, including the formation of vascular tissues. On the other hand, different cell wall compositions of xylem and phloem in different species may indicate diverse functionality and potential of substance transport, which is critical in plant evolution.
    Keywords:  autophagy; cell wall composition; conductive cells; evolution of vascular tissues; phloem; sieve elements; tracheary elements; xylem
    DOI:  https://doi.org/10.1093/aob/mcae015
  50. Cancer Lett. 2024 Feb 01. pii: S0304-3835(24)00055-7. [Epub ahead of print] 216661
    Immune checkpoints between epithelial-mesenchymal transition and autophagy: A conflicting triangle.
    Marco Cordani, Raffaele Strippoli, Flavia Trionfetti, Amir Barzegar Behrooz, Cristiano Rumio, Guillermo Velasco, Saeid Ghavami, Fabrizio Marcucci.
      Inhibitory immune checkpoint (ICP) molecules are pivotal in inhibiting innate and acquired antitumor immune responses, a mechanism frequently exploited by cancer cells to evade host immunity. These evasion strategies contribute to the complexity of cancer progression and therapeutic resistance. For this reason, ICP molecules have become targets for antitumor drugs, particularly monoclonal antibodies, collectively referred to as immune checkpoint inhibitors (ICI), that counteract such cancer-associated immune suppression and restore antitumor immune responses. Over the last decade, however, it has become clear that tumor cell-associated ICPs can also induce tumor cell-intrinsic effects, in particular epithelial-mesenchymal transition (EMT) and macroautophagy (hereafter autophagy). Both of these processes have profound implications for cancer metastasis and drug responsiveness. This article reviews the positive or negative cross-talk that tumor cell-associated ICPs undergo with autophagy and EMT. We discuss that tumor cell-associated ICPs are upregulated in response to the same stimuli that induce EMT. Moreover, ICPs themselves, when overexpressed, become an EMT-inducing stimulus. As regards the cross-talk with autophagy, ICPs have been shown to either stimulate or inhibit autophagy, while autophagy itself can either up- or downregulate the expression of ICPs. This dynamic equilibrium also extends to the autophagy-apoptosis axis, further emphasizing the complexities of cellular responses. Eventually, we delve into the intricate balance between autophagy and apoptosis, elucidating its role in the broader interplay of cellular dynamics influenced by ICPs. In the final part of this article, we speculate about the driving forces underlying the contradictory outcomes of the reciprocal, inhibitory, or stimulatory effects between ICPs, EMT, and autophagy. A conclusive identification of these driving forces may allow to achieve improved antitumor effects when using combinations of ICIs and compounds acting on EMT and/or autophagy. Prospectively, this may translate into increased and/or broadened therapeutic efficacy compared to what is currently achieved with ICI-based clinical protocols.
    Keywords:  Autophagy; Epithelial-mesenchymal transition; Immune checkpoints; Immunotherapy; PD-L1
    DOI:  https://doi.org/10.1016/j.canlet.2024.216661
  51. iScience. 2024 Feb 16. 27(2): 108893
    Lysosomal stress drives the release of pathogenic α-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway.
    Tetsuro Abe, Tomoki Kuwahara, Shoichi Suenaga, Maria Sakurai, Sho Takatori, Takeshi Iwatsubo.
      α-Synuclein and LRRK2 are associated with both familial and sporadic Parkinson's disease (PD), although the mechanistic link between these two proteins has remained elusive. Treating cells with lysosomotropic drugs causes the recruitment of LRRK2 and its substrate Rab10 onto overloaded lysosomes and induces extracellular release of lysosomal contents. Here we show that lysosomal overload elicits the release of insoluble α-synuclein from macrophages and microglia loaded with α-synuclein fibrils. This release occurred specifically in macrophage lineage cells, was dependent on the LRRK2-Rab10 pathway and involved exosomes. Also, the uptake of α-synuclein fibrils enhanced the LRRK2 phosphorylation of Rab10, which was accompanied by an increased recruitment of LRRK2 and Rab10 onto lysosomal surface. Our data collectively suggest that α-synuclein fibrils taken up in lysosomes activate the LRRK2-Rab10 pathway, which in turn upregulates the extracellular release of α-synuclein aggregates, leading to a vicious cycle that could enhance α-synuclein propagation in PD pathology.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.108893
  52. Nat Commun. 2024 Feb 06. 15(1): 1124
    Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.
    Aidan Anderson, Nada Alfahad, Dulani Wimalachandra, Kaouthar Bouzinab, Paula Rudzinska, Heather Wood, Isabel Fazey, Heping Xu, Timothy J Lyons, Nicholas M Barnes, Parth Narendran, Janet M Lord, Saaeha Rauz, Ian G Ganley, Tim M Curtis, Graham R Wallace, Jose R Hombrebueno.
      The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.
    DOI:  https://doi.org/10.1038/s41467-024-45387-9
  53. Int J Med Sci. 2024 ;21(3): 547-561
    Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome.
    Nanyang Liu, Yanqiu Ding, Hao Zhou, Xing Chang, Long Lou.
      Type-3 cardiorenal syndrome (CRS-3) is acute kidney injury followed by cardiac injury/dysfunction. Mitochondrial injury may impair myocardial function during CRS-3. Since dual-specificity phosphatase 1 (DUSP1) and prohibitin 2 (PHB2) both promote cardiac mitochondrial quality control, we assessed whether these proteins were dysregulated during CRS-3-related cardiac depression. We found that DUSP1 was downregulated in heart tissues from a mouse model of CRS-3. DUSP1 transgenic (DUSP1Tg) mice were protected from CRS-3-induced myocardial damage, as evidenced by their improved heart function and myocardial structure. CRS-3 induced the inflammatory response, oxidative stress and mitochondrial dysfunction in wild-type hearts, but not in DUSP1Tg hearts. DUSP1 overexpression normalized cardiac mitochondrial quality control during CRS-3 by suppressing mitochondrial fission, restoring mitochondrial fusion, re-activating mitophagy and augmenting mitochondrial biogenesis. We found that DUSP1 sustained cardiac mitochondrial quality control by binding directly to PHB2 and maintaining PHB2 phosphorylation, while CRS-3 disrupted this physiological interaction. Transgenic knock-in mice carrying the Phb2S91D variant were less susceptible to cardiac depression upon CRS-3, due to a reduced inflammatory response, suppressed oxidative stress and improved mitochondrial quality control in their heart tissues. Thus, CRS-3-induced myocardial dysfunction can be attributed to reduced DUSP1 expression and disrupted DUSP1/PHB2 binding, leading to defective cardiac mitochondrial quality control.
    Keywords:  CRS-3; DUSP1; PHB2; mitochondrial quality control
    DOI:  https://doi.org/10.7150/ijms.90484
  54. Cell Biol Int. 2024 Feb 05.
    M6A methylation-regulated autophagy may be a new therapeutic target for intervertebral disc degeneration.
    Yuao Tao, Xiaoyu Yu, Xiaolong Li, Yuzhu Xu, Hui Wang, Lele Zhang, Rubing Lin, Yuntao Wang, Pan Fan.
      Degeneration of intervertebral discs is considered one of the most important causes of low back pain and disability. The intervertebral disc (IVD) is characterized by its susceptibility to various stressors that accelerate the senescence and apoptosis of nucleus pulposus cells, resulting in the loss of these cells and dysfunction of the intervertebral disc. Therefore, how to reduce the loss of nucleus pulposus cells under stress environment is the main problem in treating intervertebral disc degeneration. Autophagy is a kind of programmed cell death, which can provide energy by recycling substances in cells. It is considered to be an effective method to reduce the senescence and apoptosis of nucleus pulposus cells under stress. However, further research is needed on the mechanisms by which autophagy of nucleus pulposus cells is regulated under stress environments. M6A methylation, as the most extensive RNA modification in eukaryotic cells, participates in various cellular biological functions and is believed to be related to the regulation of autophagy under stress environments, may play a significant role in nucleus pulposus responding to stress. This article first summarizes the effects of various stressors on the death and autophagy of nucleus pulposus cells. Then, it summarizes the regulatory mechanism of m6A methylation on autophagy-related genes under stress and the role of these autophagy genes in nucleus pulposus cells. Finally, it proposes that the methylation modification of autophagy-related genes regulated by m6A may become a new treatment approach for intervertebral disc degeneration, providing new insights and ideas for the clinical treatment of intervertebral disc degeneration.
    Keywords:  apoptosis; autophagy; intervertebral disc degeneration; m6A; nucleus pulposus; senescence
    DOI:  https://doi.org/10.1002/cbin.12135
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