bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–09–08
fifty-five papers selected by
Viktor Korolchuk, Newcastle University
  1. mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency.
  2. The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation.
  3. A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
  4. Spermidine controls autophagy during fasting.
  5. Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.
  6. Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.
  7. alpha-synuclein, autophagy-lysosomal pathway, and Lewy bodies: mutations, propagation, aggregation, and the formation of inclusions.
  8. Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise.
  9. The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization.
  10. Lysosome quality control in health and neurodegenerative diseases.
  11. Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders.
  12. Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer.
  13. Decoding the molecular mechanism of selective autophagy of glycogen mediated by autophagy receptor STBD1.
  14. Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
  15. Molecular mechanism and potential role of mitophagy in acute pancreatitis.
  16. Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration.
  17. Molecular mechanism of autophagy in porcine reproductive and respiratory syndrome virus infection.
  18. Sesamol-mediated targeting of EPHA2 sensitises cervical cancer for cisplatin treatment by regulating mitochondrial dynamics, autophagy, and mitophagy.
  19. Deletion of the WD40 domain of ATG16L1 exacerbates acute pancreatitis, abolishes LAP-like non-canonical autophagy and slows trypsin degradation.
  20. The multifaceted roles of selective autophagy receptors in viral infections.
  21. Autophagy in myocardial ischemia and ischemia/reperfusion.
  22. Animal amino acid sensor.
  23. ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3.
  24. Zosuquidar Promotes Antitumor Immunity by Inducing Autophagic Degradation of PD-L1.
  25. Phosphoribosyl modification of poly-ubiquitin chains at the Legionella-containing vacuole prohibiting autophagy adaptor recognition.
  26. Sde proteins coordinate ubiquitin utilization and phosphoribosylation to establish and maintain the Legionella replication vacuole.
  27. Methods for detection of cardiac glycogen-autophagy.
  28. The roles and mechanisms of endoplasmic reticulum stress-mediated autophagy in animal viral infections.
  29. Beneficial effects of rapamycin on endothelial function in systemic lupus erythematosus.
  30. The mTOR pathway controls phosphorylation of BRAF at T401.
  31. Regulation of proteostasis by sleep through autophagy in Drosophila models of Alzheimer's disease.
  32. Stat3-mediated Atg7 expression regulates anti-tumor immunity in mouse melanoma.
  33. Hsp70 Negatively Regulates Autophagy via Governing AMPK Activation, and Dual Hsp70-Autophagy Inhibition Induces Synergetic Cell Death in NSCLC Cells.
  34. Regulation of mitochondrial quality control of intestinal stem cells in homeostasis and diseases.
  35. Additional feedforward mechanism of Parkin activation via binding of phospho-UBL and RING0 in trans.
  36. Muscle-specific mitophagy: insights into hindlimb and diaphragm responses during health and sepsis.
  37. Tcap deficiency impedes striated muscle function and heart regeneration with elevated ROS and autophagy.
  38. NAFLD-associated hepatocellular carcinoma (HCC) - A compelling case for repositioning of existing mTORc1 inhibitors.
  39. Structure-activity relationship study of small-molecule inhibitor of Atg12-Atg3 protein-protein interaction.
  40. Dose-Dependent Alterations of Lysosomal Activity and Alpha-Synuclein in Peripheral Blood Monocyte-Derived Macrophages and SH-SY5Y Neuroblastoma Cell Line by upon Inhibition of MTOR Protein Kinase - Assessment of the Prospects of Parkinson's Disease Therapy.
  41. Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway.
  42. Mitophagy and cGAS-STING crosstalk in neuroinflammation.
  43. Ablation of Akt2 rescues chronic caloric restriction-provoked myocardial remodeling and dysfunction through a CDK1-mediated regulation of mitophagy.
  44. SIRT5 induces autophagy and alleviates myocardial infarction via desuccinylation of TOM1.
  45. Occupational agents-mediated asthma: From the perspective of autophagy.
  46. Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
  47. Investigating the Interplay between Mitophagy and Diabetic Neuropathy: Uncovering the hidden secrets of the disease pathology.
  48. Gaining Insight into Mitochondrial Targeting: AUTAC-Biguanide as an Anticancer Agent.
  49. TP53AIP1 induce autophagy via the AKT/mTOR signaling pathway in the breast cancer cells.
  50. Episodic Transport of Protein Aggregates Achieves a Positive Size Selectivity in Aggresome Formation.
  51. Hepatocellular carcinoma and AIM2: Therapeutic potential through regulation of autophagy and macrophage polarization.
  52. USP13 promotes acute myeloid leukemia cell proliferation and autophagy by promoting ATG5.
  53. Overexpression of RBM4 promotes acute myeloid leukemia cell differentiation by regulating alternative splicing of TFEB.
  54. Rapamycin's lifespan effect is modulated by mito-nuclear epistasis in Drosophila.
  55. A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.
  1. bioRxiv. 2024 Aug 07. pii: 2024.08.06.606942. [Epub ahead of print]
    mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency.
    Madison Lehmer, Roberto Zoncu.
      Lysosomes regulate mitochondrial function through multiple mechanisms including the master regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1) protein kinase, which is activated at the lysosomal membrane by nutrient, growth factor and energy signals. mTORC1 promotes mitochondrial protein composition changes, respiratory capacity, and dynamics, though the full range of mitochondrial-regulating functions of this protein kinase remain undetermined. We find that acute chemical modulation of mTORC1 signaling decreased mitochondrial oxygen consumption, increased mitochondrial membrane potential and reduced susceptibility to stress-induced mitophagy. In cellular models of Friedreich's Ataxia (FA), where loss of the Frataxin (FXN) protein suppresses Fe-S cluster synthesis and mitochondrial respiration, the changes induced by mTORC1 inhibitors lead to improved cell survival. Proteomic-based profiling uncover compositional changes that could underlie mTORC1-dependent modulation of FXN-deficient mitochondria. These studies highlight mTORC1 signaling as a regulator of mitochondrial composition and function, prompting further evaluation of this pathway in the context of mitochondrial disease.
    DOI:  https://doi.org/10.1101/2024.08.06.606942
  2. Nat Commun. 2024 Sep 05. 15(1): 7743
    The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation.
    Agata N Makar, Alina Boraman, Peter Mosen, Joanne E Simpson, Jair Marques, Tim Michelberger, Stuart Aitken, Ann P Wheeler, Dominic Winter, Alex von Kriegsheim, Noor Gammoh.
      Autophagy is a finely orchestrated process required for the lysosomal degradation of cytosolic components. The final degradation step is essential for clearing autophagic cargo and recycling macromolecules. Using a CRISPR/Cas9-based screen, we identify RNAseK, a highly conserved transmembrane protein, as a regulator of autophagosome degradation. Analyses of RNAseK knockout cells reveal that, while autophagosome maturation is intact, cargo degradation is severely disrupted. Importantly, lysosomal protease activity and acidification remain intact in the absence of RNAseK suggesting a specificity to autolysosome degradation. Analyses of lysosome fractions show reduced levels of a subset of hydrolases in the absence of RNAseK. Of these, the knockdown of PLD3 leads to a defect in autophagosome clearance. Furthermore, the lysosomal fraction of RNAseK-depleted cells exhibits an accumulation of the ESCRT-III complex component, VPS4a, which is required for the lysosomal targeting of PLD3. Altogether, here we identify a lysosomal hydrolase delivery pathway required for efficient autolysosome degradation.
    DOI:  https://doi.org/10.1038/s41467-024-52049-3
  3. Autophagy. 2024 Aug 30.
    A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
    Sebastian J Hofer, Ioanna Daskalaki, Mahmoud Abdellatif, Ulrich Stelzl, Simon Sedej, Nektarios Tavernarakis, Guido Kroemer, Frank Madeo.
      Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.
    Keywords:  Aging; MTOR; autophagy; lifespan; rapamycin; spermidine
    DOI:  https://doi.org/10.1080/15548627.2024.2396793
  4. Nat Aging. 2024 Sep 04.
    Spermidine controls autophagy during fasting.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00710-3
  5. bioRxiv. 2024 Aug 06. pii: 2024.08.06.606738. [Epub ahead of print]
    Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.
    Ashley Segura-Roman, Y Rose Citron, Myungsun Shin, Nicole Sindoni, Alex Maya-Romero, Simon Rapp, Claire Goul, Joseph D Mancias, Roberto Zoncu.
      Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα/β) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis, partly via its AKAP11 scaffold. Mutations in AKAP11 drive schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Through proteomic-based analysis of immunopurified lysosomes, we identify the Cα-RIα-AKAP11 holocomplex as a prominent autophagy-associated protein kinase complex. AKAP11 scaffolds Cα-RIα to the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RIα linker-hinge region as an AKAP11-dependent phospho-residue that modulates RIα-Cα binding and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters Ser83 phosphorylation, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a novel platform that modulate PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.
    DOI:  https://doi.org/10.1101/2024.08.06.606738
  6. Cell Mol Life Sci. 2024 Sep 03. 81(1): 382
    Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.
    Lijun Dai, Miao Liu, Wei Ke, Liam Chen, Xin Fang, Zhentao Zhang.
      In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function. Converging data suggest that lysosomal dysfunction is a critical event in the etiology of Parkinson's disease (PD). Mutations in Glucosylceramidase Beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for the development of parkinsonism. Furthermore, lysosomal dysfunction has been observed in the affected neurons of sporadic PD (sPD) patients. Given that lysosomal hydrolases actively contribute to the breakdown of impaired organelles and misfolded proteins, any compromise in lysosomal integrity could incite abnormal accumulation of proteins, including α-synuclein, the major component of Lewy bodies in PD. Clinical observations have shown that lysosomal protein levels in cerebrospinal fluid may serve as potential biomarkers for PD diagnosis and as signs of lysosomal dysfunction. In this review, we summarize the current evidence regarding lysosomal dysfunction in PD and discuss the intimate relationship between lysosomal dysfunction and pathological α-synuclein. In addition, we discuss therapeutic strategies that target lysosomes to treat PD.
    Keywords:  Biomarkers; Chaperone-mediated autophagy; GBA1; TMEM175; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s00018-024-05419-5
  7. J Biol Chem. 2024 Sep 02. pii: S0021-9258(24)02243-9. [Epub ahead of print] 107742
    alpha-synuclein, autophagy-lysosomal pathway, and Lewy bodies: mutations, propagation, aggregation, and the formation of inclusions.
    Armin Bayati, Peter S McPherson.
      Research into the pathophysiology of Parkinson's disease (PD) is a fast-paced pursuit, with new findings about PD and other synucleinopathies being made each year. The involvement of various lysosomal proteins, such as TFEB, TMEM175, GBA, and LAMP1/2, marks the rising awareness about the importance of lysosomes in PD and other neurodegenerative disorders. This, along with recent developments regarding the involvement of microglia and the immune system in neurogenerative diseases, has brought about a new era in neurodegeneration: the role of proinflammatory cytokines on the nervous system, and their downstream effects on mitochondria, lysosomal degradation, and autophagy. More effort is needed to understand the interplay between neuroimmunology and disease mechanisms, as many of the mechanisms remain enigmatic. α-synuclein, a key protein in PD and the main component of Lewy bodies, sits at the nexus between lysosomal degradation, autophagy, cellular stress, neuroimmunology, PD pathophysiology, and disease progression. This review revisits some fundamental knowledge about PD while capturing some of the latest trends in PD research, specifically as it relates to α-synuclein.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107742
  8. Nat Cell Biol. 2024 Aug 29.
    Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise.
    So Jung Park, Sung Min Son, Antonio Daniel Barbosa, Lidia Wrobel, Eleanna Stamatakou, Ferdinando Squitieri, Gabriel Balmus, David C Rubinsztein.
      Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens. These revealed that loss of proteasome and nuclear pore complex components cause synergistic viability changes akin to synthetic fitness loss in autophagy-null cells. This can be attributed to the cytoplasm-to-nuclear transport of proteins during autophagy deficiency and subsequent degradation of these erstwhile cytoplasmic proteins by nuclear proteasomes. As both autophagy and cytoplasm-to-nuclear transport are defective in Huntington's disease, such cells are more vulnerable to perturbations of proteostasis due to these synthetic interactions.
    DOI:  https://doi.org/10.1038/s41556-024-01488-7
  9. Cell Rep. 2024 Aug 27. pii: S2211-1247(24)01040-4. [Epub ahead of print]43(9): 114689
    The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization.
    Devanarayanan Siva Sankar, Stephanie Kaeser-Pebernard, Christine Vionnet, Sebastian Favre, Lais de Oliveira Marchioro, Benjamin Pillet, Jianwen Zhou, Michael Stumpe, Werner Josef Kovacs, Dieter Kressler, Manuela Antonioli, Gian Maria Fimia, Jӧrn Dengjel.
      Autophagy initiation is regulated by the ULK1 kinase complex. To gain insights into functions of the holo-complex, we generated a deep interactome by combining affinity purification- and proximity labeling-mass spectrometry of all four complex members: ULK1, ATG13, ATG101, and RB1CC1/FIP200. Under starvation conditions, the ULK1 complex interacts with several protein and lipid kinases and phosphatases, implying the formation of a signalosome. Interestingly, several selective autophagy receptors also interact with ULK1, indicating the activation of selective autophagy pathways by nutrient starvation. One effector of the ULK1 complex is the HSC/HSP70 co-chaperone BAG2, which regulates the subcellular localization of the VPS34 lipid kinase complex member AMBRA1. Depending on the nutritional status, BAG2 has opposing roles. In growth conditions, the unphosphorylated form of BAG2 sequesters AMBRA1, attenuating autophagy induction. In starvation conditions, ULK1 phosphorylates BAG2 on Ser31, which supports the recruitment of AMBRA1 to the ER membrane, positively affecting autophagy.
    Keywords:  AP-MS; BioID; CP: Cell biology; CP: Molecular biology; ER; autophagy; interactome; kinase; mass spectromtery; proteomics; signaling; signalosome
    DOI:  https://doi.org/10.1016/j.celrep.2024.114689
  10. Cell Mol Biol Lett. 2024 Sep 05. 29(1): 116
    Lysosome quality control in health and neurodegenerative diseases.
    Veronica Ferrari, Barbara Tedesco, Marta Cozzi, Marta Chierichetti, Elena Casarotto, Paola Pramaggiore, Laura Cornaggia, Ali Mohamed, Guglielmo Patelli, Margherita Piccolella, Riccardo Cristofani, Valeria Crippa, Mariarita Galbiati, Angelo Poletti, Paola Rusmini.
      Lysosomes are acidic organelles involved in crucial intracellular functions, including the degradation of organelles and protein, membrane repair, phagocytosis, endocytosis, and nutrient sensing. Given these key roles of lysosomes, maintaining their homeostasis is essential for cell viability. Thus, to preserve lysosome integrity and functionality, cells have developed a complex intracellular system, called lysosome quality control (LQC). Several stressors may affect the integrity of lysosomes, causing Lysosomal membrane permeabilization (LMP), in which membrane rupture results in the leakage of luminal hydrolase enzymes into the cytosol. After sensing the damage, LQC either activates lysosome repair, or induces the degradation of the ruptured lysosomes through autophagy. In addition, LQC stimulates the de novo biogenesis of functional lysosomes and lysosome exocytosis. Alterations in LQC give rise to deleterious consequences for cellular homeostasis. Specifically, the persistence of impaired lysosomes or the malfunctioning of lysosomal processes leads to cellular toxicity and death, thereby contributing to the pathogenesis of different disorders, including neurodegenerative diseases (NDs). Recently, several pieces of evidence have underlined the importance of the role of lysosomes in NDs. In this review, we describe the elements of the LQC system, how they cooperate to maintain lysosome homeostasis, and their implication in the pathogenesis of different NDs.
    Keywords:  Galectins; Lysosomal membrane permeabilization; Lysosome; Lysosome quality control; Neurodegeneration
    DOI:  https://doi.org/10.1186/s11658-024-00633-2
  11. Mol Psychiatry. 2024 Sep 06.
    Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders.
    Ahrom Ham, Audrey Yuen Chang, Hongyu Li, Jennifer M Bain, James E Goldman, David Sulzer, Jeremy Veenstra-VanderWeele, Guomei Tang.
      Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lympoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.
    DOI:  https://doi.org/10.1038/s41380-024-02741-z
  12. Cell Death Discov. 2024 Sep 03. 10(1): 393
    Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer.
    Wenjing Xue, Caili Xu, Kaiqi Zhang, Lu Cui, Xiting Huang, Yanyang Nan, Dianwen Ju, Xusheng Chang, Xuyao Zhang.
      Claudin18.2 (CLDN18.2) is overexpressed in cancers of the digestive system, rendering it an ideal drug target for antibody-drug conjugates (ADCs). Despite many CLDN18.2-directed ADCs undergoing clinical trials, the inconclusive underlying mechanisms pose a hurdle to extending the utility of these agents. In our study, αCLDN18.2-MMAE, an ADC composed of an anti-CLDN18.2 monoclonal antibody and the tubulin inhibitor MMAE, induced a dose-dependent apoptosis via the cleavage of caspase-9/PARP proteins in CLDN18.2-positive gastric cancer cells. It was worth noting that autophagy was remarkably activated during the αCLDN18.2-MMAE treatment, which was characterized by the accumulation of autophagosomes, the conversion of autophagy marker LC3 from its form I to II, and the complete autophagic flux. Inhibiting autophagy by autophagy inhibitor LY294002 remarkably enhanced αCLDN18.2-MMAE-induced cytotoxicity and caspase-mediated apoptosis, indicating the cytoprotective role of autophagy in CLDN18.2-directed ADC-treated gastric cancer cells. Combination with an autophagy inhibitor significantly potentiated the in vivo antitumoral efficacy of αCLDN18.2-MMAE. Besides, the Akt/mTOR pathway inactivation was demonstrated to be implicated in the autophagy initiation in αCLDN18.2-MMAE-treated gastric cancer cells. In conclusion, our study highlighted a groundbreaking investigation into the mechanism of the CLDN18.2-directed ADC, focusing on the crucial role of autophagy, providing a novel insight to treat gastric cancer by the combination of CLDN18.2-directed ADC and autophagy inhibitor.
    DOI:  https://doi.org/10.1038/s41420-024-02167-0
  13. Proc Natl Acad Sci U S A. 2024 Sep 10. 121(37): e2402817121
    Decoding the molecular mechanism of selective autophagy of glycogen mediated by autophagy receptor STBD1.
    Yuchao Zhang, Yishan Sun, Jungang Shi, Peng Xu, Yingli Wang, Jianping Liu, Xinyu Gong, Yaru Wang, Yubin Tang, Haobo Liu, Xindi Zhou, Zhiqiao Lin, Otto Baba, Tsuyoshi Morita, Biao Yu, Lifeng Pan.
      Autophagy of glycogen (glycophagy) is crucial for the maintenance of cellular glucose homeostasis and physiology in mammals. STBD1 can serve as an autophagy receptor to mediate glycophagy by specifically recognizing glycogen and relevant key autophagic factors, but with poorly understood mechanisms. Here, we systematically characterize the interactions of STBD1 with glycogen and related saccharides, and determine the crystal structure of the STBD1 CBM20 domain with maltotetraose, uncovering a unique binding mode involving two different oligosaccharide-binding sites adopted by STBD1 CBM20 for recognizing glycogen. In addition, we demonstrate that the LC3-interacting region (LIR) motif of STBD1 can selectively bind to six mammalian ATG8 family members. We elucidate the detailed molecular mechanism underlying the selective interactions of STBD1 with ATG8 family proteins by solving the STBD1 LIR/GABARAPL1 complex structure. Importantly, our cell-based assays reveal that both the STBD1 LIR/GABARAPL1 interaction and the intact two oligosaccharide binding sites of STBD1 CBM20 are essential for the effective association of STBD1, GABARAPL1, and glycogen in cells. Finally, through mass spectrometry, biochemical, and structural modeling analyses, we unveil that STBD1 can directly bind to the Claw domain of RB1CC1 through its LIR, thereby recruiting the key autophagy initiation factor RB1CC1. In all, our findings provide mechanistic insights into the recognitions of glycogen, ATG8 family proteins, and RB1CC1 by STBD1 and shed light on the potential working mechanism of STBD1-mediated glycophagy.
    Keywords:  GABARAPL1; RB1CC1; STBD1; glycogen; glycophagy
    DOI:  https://doi.org/10.1073/pnas.2402817121
  14. Autophagy. 2024 Sep 03. 1-3
    Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
    Hao Liu, Jianming Xie, Cien Zhen, Lin Zeng, Hualin Fan, Haixia Zhuang, Du Feng.
      Mitochondria, the powerhouses of the cell, play pivotal roles in cellular processes ranging from energy production to innate immunity. Their unique double-membrane structure typically sequesters mitochondrial DNA (mtDNA) from the rest of the cell. However, under oxidative or immune stress, mtDNA can escape into the cytoplasm, posing a threat as a potential danger signal. The accumulation of cytoplasmic mtDNA can disrupt cellular immune balance and trigger cell death. Our research unveils a novel quality control mechanism, which we term "nucleoid-phagy", that safeguards cellular homeostasis by clearing mislocalized mtDNA. We demonstrate that TFAM, a key protein involved in mtDNA folding and wrapping, accompanies mtDNA into the cytoplasm under stress conditions. Remarkably, TFAM acts as an autophagy receptor, interacting with LC3B to facilitate the autophagic clearance of cytoplasmic mtDNA, thereby preventing the activation of the pro-inflammatory CGAS-STING1 pathway. This study provides unprecedented insights into cytoplasmic mtDNA quality control and offers new perspectives on mitigating inflammatory responses in mitochondrial-related diseases.
    Keywords:  Autophagy; CGAS-STING1; LIR; TFAM; mitochondria DNA
    DOI:  https://doi.org/10.1080/15548627.2024.2395145
  15. Mol Med. 2024 Sep 03. 30(1): 136
    Molecular mechanism and potential role of mitophagy in acute pancreatitis.
    Lili Zhu, Yunfei Xu, Jian Lei.
      Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder.
    Keywords:  Lysosome; Mitochondrial dysfunction; Mitophagosome; Mitophagy; Pancreatitis
    DOI:  https://doi.org/10.1186/s10020-024-00903-x
  16. Autophagy. 2024 Aug 30.
    Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration.
    Zhangrong Cheng, Weikang Gan, Qian Xiang, Kangcheng Zhao, Haiyang Gao, Yuhang Chen, Pengzhi Shi, Anran Zhang, Gaocai Li, Yu Song, Xiaobo Feng, Cao Yang, Yukun Zhang.
      Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of Lamp2a or knockdown of Plcg1. Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value.
    Keywords:  Calcium overload; chaperone-mediated autophagy; intervertebral disc degeneration; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2395797
  17. Front Cell Infect Microbiol. 2024 ;14 1434775
    Molecular mechanism of autophagy in porcine reproductive and respiratory syndrome virus infection.
    Xiaoyong Chen, Ziding Yu, Wenfeng Li.
      Porcine reproductive and respiratory syndrome virus (PRRSV), a significant pathogen affecting the swine industry globally, has been shown to manipulate host cell processes, including autophagy, to facilitate its replication and survival within the host. Autophagy, an intracellular degradation process crucial for maintaining cellular homeostasis, can be hijacked by viruses for their own benefit. During PRRSV infection, autophagy plays a complex role, both as a defense mechanism of the host and as a tool exploited by the virus. This review explores the current understanding of the molecular mechanisms underlying autophagy induction under PRRSV infection, its impact on virus replication, and the potential implications for viral pathogenesis and antiviral strategies. By synthesizing the latest research findings, this article aims to enhance our understanding of the intricate relationship between autophagy and PRRSV, paving the way for novel therapeutic approaches against this swine pathogen.
    Keywords:  autophagy; cellular factors; porcine reproductive and respiratory syndrome virus; viral proteins; virus-host interaction
    DOI:  https://doi.org/10.3389/fcimb.2024.1434775
  18. Mol Biol Rep. 2024 Sep 02. 51(1): 949
    Sesamol-mediated targeting of EPHA2 sensitises cervical cancer for cisplatin treatment by regulating mitochondrial dynamics, autophagy, and mitophagy.
    P P Mubthasima, Sridevi Annapurna Singh, Anbarasu Kannan.
       BACKGROUND: Cervical cancer ranks as the fourth most prevalent cancer among women globally, presenting a significant therapeutic challenge due to its resistance to cisplatin. Ephrin type-A receptor 2 (EPHA2) is prominently overexpressed in cervical cancer and plays a vital role in cisplatin resistance, although the underlying mechanisms remain incompletely elucidated. Mitochondrial dynamics, autophagy, and mitophagy are critical in mediating cisplatin resistance. Sesamol, a phytochemical compound, has exhibited promising anticancer properties. This study aims to investigate the regulatory role of EPHA2 in these pathways underlying cisplatin resistance and to investigate the potential of sesamol in overcoming this resistance and inhibiting cervical cancer progression.
    METHODS AND RESULT: In this study, we knocked down EPHA2 in the SiHa cell line and evaluated the resulting changes in molecular markers associated with mitochondrial dynamics, mitophagy, and autophagy. Our results indicated that EPHA2 knockdown (EPHA2-KD) led to enhanced mitochondrial fusion and reduced mitochondrial fission, mitophagy, and autophagy. Furthermore, we investigated the effect of EPHA2-KD and sesamol treatment on sensitising cervical cancer to cisplatin treatment. Our data revealed that EPHA2-KD and sesamol treatment significantly increases cellular sensitivity to cisplatin-induced cytotoxicity. Additionally, we demonstrated that sesamol effectively targets EPHA2, as evidenced by decreased EPHA2 expression levels following sesamol treatment.
    CONCLUSION: In summary, targeting EPHA2 through knockdown or sesamol treatment enhances cisplatin sensitivity in cervical cancer by modulating mitochondrial dynamics, autophagy and mitophagy, suggesting promising therapeutic strategies to overcome chemoresistance.
    Keywords:  Autophagy; EPHA2; Mitochondrial dynamics; Mitophagy; Sesamol
    DOI:  https://doi.org/10.1007/s11033-024-09875-x
  19. Autophagy. 2024 Aug 31. 1-13
    Deletion of the WD40 domain of ATG16L1 exacerbates acute pancreatitis, abolishes LAP-like non-canonical autophagy and slows trypsin degradation.
    Michael Chvanov, Svetlana Voronina, Matthew Jefferson, Ulrike Mayer, Robert Sutton, David N Criddle, Thomas Wileman, Alexei V Tepikin.
      The WD40 domain (WDD) of ATG16L1 plays a pivotal role in non-canonical autophagy. This study examined the role of recently identified LAP-like non-canonical autophagy (LNCA) in acute pancreatitis. LNCA involves rapid single-membrane LC3 conjugation to endocytic vacuoles in pancreatic acinar cells. The rationale for this study was the previously observed presence of trypsin in the organelles undergoing LNCA; aberrant trypsin formation is an important factor in pancreatitis development. Here we report that the deletion of WDD (attained in ATG16L1[E230] mice) eliminated LNCA, aggravated caerulein-induced acute pancreatitis and suppressed the fast trypsin degradation observed in both a rapid caerulein-induced disease model and in caerulein-treated isolated pancreatic acinar cells. These experiments indicate that LNCA is a WDD-dependent mechanism and suggest that it plays not an activating but a protective role in acute pancreatitis. Furthermore, palmitoleic acid, another inducer of experimental acute pancreatitis, strongly inhibited LNCA, suggesting a novel mechanism of pancreatic lipotoxicity.Abbreviation: AMY: amylase; AP: acute pancreatitis; CASM: conjugation of Atg8 to single membranes; CCK: cholecystokinin; FAEE model: fatty acid and ethanol model; IL6: interleukin 6; LA: linoleic acid; LAP: LC3-associated phagocytosis; LMPO: lung myeloperoxidase; LNCA: LAP-like non-canonical autophagy; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MPO: myeloperoxidase; PMPO: pancreatic myeloperoxidase; POA: palmitoleic acid; WDD: WD40 domain; WT: wild type.
    Keywords:  Amylase; LC3-associated phagocytosis; caerulein; cholecystokinin; endocytic vacuoles; palmitoleic acid
    DOI:  https://doi.org/10.1080/15548627.2024.2392478
  20. J Virol. 2024 Aug 30. e0081424
    The multifaceted roles of selective autophagy receptors in viral infections.
    Rui Luo, Tao Wang, Jing Lan, Zhanhao Lu, Shengmei Chen, Yuan Sun, Hua-Ji Qiu.
      Selective autophagy is a protein clearance mechanism mediated by evolutionarily conserved selective autophagy receptors (SARs), which specifically degrades misfolded, misassembled, or metabolically regulated proteins. SARs help the host to suppress viral infections by degrading viral proteins. However, viruses have evolved sophisticated mechanisms to counteract, evade, or co-opt autophagic processes, thereby facilitating viral replication. Therefore, this review aims to summarize the complex mechanisms of SARs involved in viral infections, specifically focusing on how viruses exploit strategies to regulate selective autophagy. We present an updated understanding of the various critical roles of SARs in viral pathogenesis. Furthermore, newly discovered evasion strategies employed by viruses are discussed and the ubiquitination-autophagy-innate immune regulatory axis is proposed to be a crucial pathway to control viral infections. This review highlights the remarkable flexibility and plasticity of SARs in viral infections.
    Keywords:  innate immunity; selective autophagy; selective autophagy receptors; ubiquitination; viral infections
    DOI:  https://doi.org/10.1128/jvi.00814-24
  21. Cardiovasc Pathol. 2024 Aug 30. pii: S1054-8807(24)00087-5. [Epub ahead of print] 107691
    Autophagy in myocardial ischemia and ischemia/reperfusion.
    Aleksandra Aljakna Khan, Sara Sabatasso.
      Myocardial infarction (MI) is a life-threatening condition that leads to loss of viable heart tissue. The best way to treat acute MI and limit the infarct size is to re-open the occluded coronary artery and restore the supply of oxygenated and nutrient-rich blood, but reperfusion can cause additional damage. Autophagy is an intracellular process that recycles damaged cytoplasmic components (molecules and organelles) by loading them into autophagosomes and degrading them in autolysosomes. Autophagy is increased in in vivo animal models of permanent ischemia and ischemia/reperfusion but by different molecular mechanisms. While autophagy is protective during permanent ischemia, it is detrimental during ischemia/reperfusion. Its modulation is being investigated as a potential target to reduce reperfusion injury. This review provides a synopsis of the current knowledge about autophagy, summarizes findings specifically in permanent ischemia and ischemia/reperfusion, and briefly discusses the potential implication of experimental findings.
    Keywords:  Acute myocardial infarction; Autophagy; Autopsy; Early myocardial ischemia; Ischemia/reperfusion; Pathology; Sudden cardiac death
    DOI:  https://doi.org/10.1016/j.carpath.2024.107691
  22. Anim Biosci. 2024 Aug 26.
    Animal amino acid sensor.
    Yongding Ke, Xinyu Peng, Chengchuang Song, Xingtang Fang, Yanhong Wang, Chunlei Zhang.
      Cell growth and metabolism necessitate the involvement of amino acids, which are sensed and integrated by the mammalian target of rapamycin complex 1 (mTORC1). However, the molecular mechanisms underlying amino acid sensing remain poorly understood. Research indicates that amino acids are detected by specific sensors, with the signals being relayed to mTORC1 indirectly. This paper reviews the structures and biological functions of the amino acid sensors identified thus far. Additionally, it evaluates the potential role these sensors play in the developmental changes of the livestock production.
    Keywords:  Amino Acid Sensor; Livestock; Mammalian Target of Rapamycin
    DOI:  https://doi.org/10.5713/ab.24.0366
  23. Autophagy. 2024 Sep 03. 1-14
    ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3.
    Shuai Yang, Mengqiu Li, Guangyu Lian, Yaoxing Wu, Jun Cui, Liqiu Wang.
      The NLRP3 inflammasome is a multiprotein complex that plays a vital role in the innate immune system in response to microbial infections and endogenous danger signals. Aberrant activation of the NLRP3 inflammasome is implicated in a spectrum of inflammatory and autoimmune diseases, emphasizing the necessity for precise regulation of the NLRP3 inflammasome to maintain immune homeostasis. The protein level of NLRP3 is a limiting step for inflammasome activation, which must be tightly controlled to avoid detrimental consequences. Here, we demonstrate that ABHD8, a member of the α/β-hydrolase domain-containing (ABHD) family, interacts with NLRP3 and promotes its degradation through the chaperone-mediated autophagy (CMA) pathway. ABHD8 acts as a scaffold to recruit palmitoyltransferase ZDHHC12 to NLRP3 for its palmitoylation as well as subsequent CMA-mediated degradation. Notably, ABHD8 deficiency results in the stabilization of NLRP3 protein and promotes NLRP3 inflammasome activation. We further confirm that ABHD8 overexpression ameliorates LPS- or alum-triggered NLRP3 inflammasome activation in vivo. Interestingly, the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs the ABHD8-NLRP3 association, resulting in an elevation in NLRP3 protein level and excessive inflammasome activation. These findings demonstrate that ABHD8 May represent a potential therapeutic target in conditions associated with NLRP3 inflammasome dysregulation.Abbreviations: 3-MA: 3-methyladenine; ABHD: α/β-hydrolase domain-containing; BMDMs: Bone marrow-derived macrophages; CFZ: carfilzomib; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DAMPs: danger/damage-associated molecular patterns; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; NH4Cl: ammonium chloride; NLRP3: NLR family pyrin domain containing 3; PAMPs: pathogen-associated molecular patterns; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
    Keywords:  ABHD8; CMA; NLRP3; inflammasome; palmitoylation
    DOI:  https://doi.org/10.1080/15548627.2024.2395158
  24. Adv Sci (Weinh). 2024 Sep 04. e2400340
    Zosuquidar Promotes Antitumor Immunity by Inducing Autophagic Degradation of PD-L1.
    Ling Ding, Hongjie Guo, Jie Zhang, Mingming Zheng, Wenjie Zhang, Longsheng Wang, Qianqian Du, Chen Zhou, Yanjun Xu, Honghai Wu, Qiaojun He, Bo Yang.
      The intracellular distribution and transportation process are essential for maintaining PD-L1 (programmed death-ligand 1) expression, and intervening in this cellular process may provide promising therapeutic strategies. Here, through a cell-based high content screening, it is found that the ABCB1 (ATP binding cassette subfamily B member 1) modulator zosuquidar dramatically suppresses PD-L1 expression by triggering its autophagic degradation. Mechanistically, ABCB1 interacts with PD-L1 and impairs COP II-mediated PD-L1 transport from ER (endoplasmic reticulum) to Golgi apparatus. The treatment of zosuquidar enhances ABCB1-PD-L1 interaction and leads the ER retention of PD-L1, which is subsequently degraded in the SQSTM1-dependent selective autophagy pathway. In CT26 mouse model and a humanized xenograft mouse model, zosuquidar significantly suppresses tumor growth and accompanies by increased infiltration of cytotoxic T cells. In summary, this study indicates that ABCB1 serves as a negative regulator of PD-L1, and zosuquidar may act as a potential immunotherapy agent by triggering PD-L1 degradation in the early secretory pathway.
    Keywords:  ABCB1; ER retention; PD‐L1; autophagy; zosuquidar
    DOI:  https://doi.org/10.1002/advs.202400340
  25. Nat Commun. 2024 Aug 30. 15(1): 7481
    Phosphoribosyl modification of poly-ubiquitin chains at the Legionella-containing vacuole prohibiting autophagy adaptor recognition.
    Min Wan, Marena E Minelli, Qiuye Zhao, Shannon Marshall, Haiyuan Yu, Marcus Smolka, Yuxin Mao.
      Ubiquitination is a posttranslational modification in eukaryotes that plays a significant role in the infection of intracellular microbial pathogens, such as Legionella pneumophila. While the Legionella-containing vacuole (LCV) is coated with ubiquitin (Ub), it avoids recognition by autophagy adaptors. Here, we report that the Sdc and Sde families of effectors work together to build ubiquitinated species around the LCV. The Sdc effectors catalyze canonical polyubiquitination directly on host targets or on phosphoribosyl-Ub conjugated to host targets by Sde. Remarkably, Ub moieties within poly-Ub chains are either modified with a phosphoribosyl group by PDE domain-containing effectors or covalently attached to other host substrates via Sde-mediated phosphoribosyl-ubiquitination. Furthermore, these modifications prevent the recognition by Ub adaptors and therefore exclude host autophagy adaptors from the LCV. In this work, we shed light on the nature of the poly-ubiquitinated species present at the surface of the LCV and provide a molecular mechanism for the avoidance of autophagy adaptors by the Ub-decorated LCV.
    DOI:  https://doi.org/10.1038/s41467-024-51273-1
  26. Nat Commun. 2024 Aug 30. 15(1): 7479
    Sde proteins coordinate ubiquitin utilization and phosphoribosylation to establish and maintain the Legionella replication vacuole.
    Kristin M Kotewicz, Mengyun Zhang, Seongok Kim, Meghan S Martin, Atish Roy Chowdhury, Albert Tai, Rebecca A Scheck, Ralph R Isberg.
      The Legionella pneumophila Sde family of translocated proteins promotes host tubular endoplasmic reticulum (ER) rearrangements that are tightly linked to phosphoribosyl-ubiquitin (pR-Ub) modification of Reticulon 4 (Rtn4). Sde proteins have two additional activities of unclear relevance to the infection process: K63 linkage-specific deubiquitination and phosphoribosyl modification of polyubiquitin (pR-Ub). We show here that the deubiquitination activity (DUB) stimulates ER rearrangements while pR-Ub protects the replication vacuole from cytosolic surveillance by autophagy. Loss of DUB activity is tightly linked to lowered pR-Ub modification of Rtn4, consistent with the DUB activity fueling the production of pR-Ub-Rtn4. In parallel, phosphoribosyl modification of polyUb, in a region of the protein known as the isoleucine patch, prevents binding by the autophagy adapter p62. An inability of Sde mutants to modify polyUb results in immediate p62 association, a critical precursor to autophagic attack. The ability of Sde WT to block p62 association decays quickly after bacterial infection, as predicted by the presence of previously characterized L. pneumophila effectors that inactivate Sde and remove polyUb. In sum, these results show that the accessory Sde activities act to stimulate ER rearrangements and protect from host innate immune sensing in a temporal fashion.
    DOI:  https://doi.org/10.1038/s41467-024-51272-2
  27. bioRxiv. 2024 Aug 11. pii: 2024.08.11.607511. [Epub ahead of print]
    Methods for detection of cardiac glycogen-autophagy.
    Parisa Koutsifeli, Lorna J Daniels, Joshua Neale, Sarah Fong, Upasna Varma, Marco Annandale, Xun Li, Yohanes Nursalim, James R Bell, Kate L Weeks, Aleksandr Stotland, David J Taylor, Roberta A Gottlieb, Lea M D Delbridge, Kimberley M Mellor.
      Glycogen-autophagy ('glycophagy') is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.
    DOI:  https://doi.org/10.1101/2024.08.11.607511
  28. Vet Res. 2024 Sep 03. 55(1): 107
    The roles and mechanisms of endoplasmic reticulum stress-mediated autophagy in animal viral infections.
    Lan Chen, Miaozhan Wei, Bijun Zhou, Kaigong Wang, Erpeng Zhu, Zhentao Cheng.
      The endoplasmic reticulum (ER) is a unique organelle responsible for protein synthesis and processing, lipid synthesis in eukaryotic cells, and the replication of many animal viruses is closely related to ER. A considerable number of viral proteins are synthesised during viral infection, resulting in the accumulation of unfolded and misfolded proteins in ER, which in turn induces endoplasmic reticulum stress (ERS). ERS further drives three signalling pathways (PERK, IRE1, and ATF6) of the cellular unfolded protein response (UPR) to respond to the ERS. In numerous studies, ERS has been shown to mediate autophagy, a highly conserved cellular degradation mechanism to maintain cellular homeostasis in eukaryotic cells, through the UPR to restore ER homeostasis. ERS-mediated autophagy is closely linked to the occurrence and development of numerous viral diseases in animals. Host cells can inhibit viral replication by regulating ERS-mediated autophagy, restoring the ER's normal physiological process. Conversely, many viruses have evolved strategies to exploit ERS-mediated autophagy to achieve immune escape. These strategies include the regulation of PERK-eIF2α-Beclin1, PERK-eIF2α-ATF4-ATG12, IRE1α-JNK-Beclin1, and other signalling pathways, which provide favourable conditions for the replication of animal viruses in host cells. The ERS-mediated autophagy pathway has become a hot topic in animal virological research. This article reviews the most recent research regarding the regulatory functions of ERS-mediated autophagy pathways in animal viral infections, emphasising the underlying mechanisms in the context of different viral infections. Furthermore, it considers the future direction and challenges in the development of ERS-mediated autophagy targeting strategies for combating animal viral diseases, which will contribute to unveiling their pathogenic mechanism from a new perspective and provide a scientific reference for the discovery and development of new antiviral drugs and preventive strategies.
    Keywords:  Endoplasmic reticulum stress (ERS); animal viruses; autophagy; cellular unfolded protein response (UPR); immune escape
    DOI:  https://doi.org/10.1186/s13567-024-01360-4
  29. Front Physiol. 2024 ;15 1446836
    Beneficial effects of rapamycin on endothelial function in systemic lupus erythematosus.
    Hyoseon Kim, Michael P Massett.
       Introduction: Endothelial function is significantly impaired in patients with SLE compared to healthy controls. Elevated activation of the mammalian target of rapamycin complex 1 (mTORC1) is reported in humans and mice with SLE. However, it is unclear if elevated mTORC1 in SLE contributes to impaired mitophagy and endothelial dysfunction. Therefore, we tested the hypothesis that inhibiting mTORC1 with rapamycin would increase mitophagy and attenuate endothelial dysfunction and inflammatory responses in SLE.
    Methods: Nine-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned into rapamycin treatment (lpr_Rapamycin and MpJ_Rapamycin) or control (lpr_Control and MpJ_Control) groups. Rapamycin was injected i.p. 3 days per week for 8 weeks. After 8 weeks, endothelium-dependent vasorelaxation to acetylcholine (ACh) and endothelium-independent vasorelaxation to sodium nitroprusside (SNP) were measured in thoracic aortas using a wire myograph.
    Results: MTORC1 activity was increased in aorta from lpr mice as demonstrated by increased phosphorylation of s6rp and p70s6k and significantly inhibited by rapamycin (s6rp, p < 0.0001, p70s6k, p = 0.04, respectively). Maximal responses to Ach were significantly impaired in lpr_Control (51.7% ± 6.6%) compared to MpJ_Control (86.7% ± 3.6%) (p < 0.0001). Rapamycin prevented endothelial dysfunction in the thoracic aorta from lupus mice (lpr_Rapamycin) (79.6% ± 4.2%) compared to lpr_Control (p = 0.002). Maximal responses to SNP were not different across groups. Phosphorylation of endothelial nitric oxide synthase also was 42% lower in lpr_Control than MpJ_Control and 46% higher in lpr_Rapamycin than lpr_Control. The inflammatory marker, vascular cell adhesion protein 1 (Vcam 1), was elevated in aorta from lupus mice compared with healthy mice (p = 0.001), and significantly reduced with Rapamycin treatment (p = 0.0021). Mitophagy markers were higher in lupus mice and reduced by rapamycin treatment, suggesting altered mitophagy in lpr mice.
    Conclusion: Collectively, these results demonstrate the beneficial effects of inhibiting mTORC1 on endothelial function in SLE mice and suggest inflammation and altered mitophagy contribute to endothelial dysfunction in SLE.
    Keywords:  inflammatory response; lpr mice; mTORC1 inhibition; mitophagy; mouse aorta; vascular function
    DOI:  https://doi.org/10.3389/fphys.2024.1446836
  30. Cell Commun Signal. 2024 Sep 02. 22(1): 428
    The mTOR pathway controls phosphorylation of BRAF at T401.
    Daniel Christen, Manuel Lauinger, Melanie Brunner, Jörn Dengjel, Tilman Brummer.
      BRAF serves as a gatekeeper of the RAS/RAF/MEK/ERK pathway, which plays a crucial role in homeostasis. Since aberrant signalling of this axis contributes to cancer and other diseases, it is tightly regulated by crosstalk with the PI3K/AKT/mTOR pathway and ERK mediated feedback loops. For example, ERK limits BRAF signalling through phosphorylation of multiple residues. One of these, T401, is widely considered as an ERK substrate following acute pathway activation by growth factors. Here, we demonstrate that prominent T401 phosphorylation (pT401) of endogenous BRAF is already observed in the absence of acute stimulation in various cell lines of murine and human origin. Importantly, the BRAF/RAF1 inhibitor naporafenib, the MEK inhibitor trametinib and the ERK inhibitor ulixertinib failed to reduce pT401 levels in these settings, supporting an alternative ERK-independent pathway to T401 phosphorylation. In contrast, the mTOR inhibitor torin1 and the dual-specific PI3K/mTOR inhibitor dactolisib significantly suppressed pT401 levels in all investigated cell types, in both a time and concentration dependent manner. Conversely, genetic mTOR pathway activation by oncogenic RHEB (Q64L) and mTOR (S2215Y and R2505P) mutants substantially increased pT401, an effect that was reverted by dactolisib and torin1 but not by trametinib. We also show that shRNAmir mediated depletion of the mTORC1 complex subunit Raptor significantly enhanced the suppression of T401 phosphorylation by a low torin1 dose, while knockdown of the mTORC2 complex subunit Rictor was less effective. Using mass spectrometry, we provide further evidence that torin1 suppresses the phosphorylation of T401, S405 and S409 but not of other important regulatory phosphorylation sites such as S446, S729 and S750. In summary, our data identify the mTOR axis and its inhibitors of (pre)clinical relevance as novel modulators of BRAF phosphorylation at T401.
    DOI:  https://doi.org/10.1186/s12964-024-01808-2
  31. Life Sci Alliance. 2024 Nov;pii: e202402681. [Epub ahead of print]7(11):
    Regulation of proteostasis by sleep through autophagy in Drosophila models of Alzheimer's disease.
    Natalie Ortiz-Vega, Amanda G Lobato, Tijana Canic, Yi Zhu, Stanislav Lazopulo, Sheyum Syed, R Grace Zhai.
      Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer's disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD; however, the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration in Drosophila models of tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.
    DOI:  https://doi.org/10.26508/lsa.202402681
  32. Cancer Immunol Immunother. 2024 Sep 05. 73(11): 218
    Stat3-mediated Atg7 expression regulates anti-tumor immunity in mouse melanoma.
    Sarah M Zimmerman, Erin Suh, Sofia R Smith, George P Souroullas.
      Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2Y641F interacts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by Ezh2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models, we further investigated the role of pathways downstream of Ezh2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of a wild-type or Ezh2Y641F epigenetic state. We found that the Atg7 locus is controlled by multiple Ezh2 and Stat3 binding sites, Atg7 expression is dependent on Stat3 expression, and that deletion of Atg7 slows down melanoma cell growth in vivo, but not in vitro. Atg7 deletion also results in increased CD8 + T cells in Ezh2Y641F melanomas and reduced myelosuppressive cell infiltration in the tumor microenvironment, particularly in Ezh2WT melanomas, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.
    Keywords:  Atg7; Autophagy; Melanoma; Tumor-immune response
    DOI:  https://doi.org/10.1007/s00262-024-03804-4
  33. Int J Mol Sci. 2024 Aug 22. pii: 9090. [Epub ahead of print]25(16):
    Hsp70 Negatively Regulates Autophagy via Governing AMPK Activation, and Dual Hsp70-Autophagy Inhibition Induces Synergetic Cell Death in NSCLC Cells.
    Bashar Alhasan, Yana A Gladova, Dmitry V Sverchinsky, Nikolai D Aksenov, Boris A Margulis, Irina V Guzhova.
      Proteostasis mechanisms, such as proteotoxic-stress response and autophagy, are increasingly recognized for their roles in influencing various cancer hallmarks such as tumorigenesis, drug resistance, and recurrence. However, the precise mechanisms underlying their coordination remain not fully elucidated. The aim of this study is to investigate the molecular interplay between Hsp70 and autophagy in lung adenocarcinoma cells and elucidate its impact on the outcomes of anticancer therapies in vitro. For this purpose, we utilized the human lung adenocarcinoma A549 cell line and genetically modified it by knockdown of Hsp70 or HSF1, and the H1299 cell line with knockdown or overexpression of Hsp70. In addition, several treatments were employed, including treatment with Hsp70 inhibitors (VER-155008 and JG-98), HSF1 activator ML-346, or autophagy modulators (SAR405 and Rapamycin). Using immunoblotting, we found that Hsp70 negatively regulates autophagy by directly influencing AMPK activation, uncovering a novel regulatory mechanism of autophagy by Hsp70. Genetic or chemical Hsp70 overexpression was associated with the suppression of AMPK and autophagy. Conversely, the inhibition of Hsp70, genetically or chemically, resulted in the upregulation of AMPK-mediated autophagy. We further investigated whether Hsp70 suppression-mediated autophagy exhibits pro-survival- or pro-death-inducing effects via MTT test, colony formation, CellTiter-Glo 3D-Spheroid viability assay, and Annexin/PI apoptosis assay. Our results show that combined inhibition of Hsp70 and autophagy, along with cisplatin treatment, synergistically reduces tumor cell metabolic activity, growth, and viability in 2D and 3D tumor cell models. These cytotoxic effects were exerted by substantially potentiating apoptosis, while activating autophagy via rapamycin slightly rescued tumor cells from apoptosis. Therefore, our findings demonstrate that the combined inhibition of Hsp70 and autophagy represents a novel and promising therapeutic approach that may disrupt the capacity of refractory tumor cells to withstand conventional therapies in NSCLC.
    Keywords:  AMPK; Hsp70; autophagy; cancer; combinatorial cancer therapy; drug resistance; mTOR; proteostasis
    DOI:  https://doi.org/10.3390/ijms25169090
  34. Antioxid Redox Signal. 2024 Sep 03.
    Regulation of mitochondrial quality control of intestinal stem cells in homeostasis and diseases.
    Xudan Lei, Zhenni Xu, Yujun Huang, Lingxiao Huang, Jinyi Lang, Mingyue Qu, Dengqun Liu.
       SIGNIFICANCE: Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases.
    RECENT ADVANCES: In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating of ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological condition and protects against intestinal injury remains to be comprehensively reviewed.
    CRITICAL ISSUES: In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy and proteostasis impact ISC proliferation, differentiation and regeneration, respectively.
    FUTURE DIRECTIONS: We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases.
    DOI:  https://doi.org/10.1089/ars.2023.0489
  35. Elife. 2024 Sep 02. pii: RP96699. [Epub ahead of print]13
    Additional feedforward mechanism of Parkin activation via binding of phospho-UBL and RING0 in trans.
    Dipti Ranjan Lenka, Shakti Virendra Dahe, Odetta Antico, Pritiranjan Sahoo, Alan R Prescott, Miratul M K Muqit, Atul Kumar.
      Loss-of-function Parkin mutations lead to early-onset of Parkinson's disease. Parkin is an auto-inhibited ubiquitin E3 ligase activated by dual phosphorylation of its ubiquitin-like (Ubl) domain and ubiquitin by the PINK1 kinase. Herein, we demonstrate a competitive binding of the phospho-Ubl and RING2 domains towards the RING0 domain, which regulates Parkin activity. We show that phosphorylated Parkin can complex with native Parkin, leading to the activation of autoinhibited native Parkin in trans. Furthermore, we show that the activator element (ACT) of Parkin is required to maintain the enzyme kinetics, and the removal of ACT slows the enzyme catalysis. We also demonstrate that ACT can activate Parkin in trans but less efficiently than when present in the cis molecule. Furthermore, the crystal structure reveals a donor ubiquitin binding pocket in the linker connecting REP and RING2, which plays a crucial role in Parkin activity.
    Keywords:  E. coli; Parkin E3 ligase; Parkinson's disease; Ubiquitin; molecular biophysics; structural biology; structure
    DOI:  https://doi.org/10.7554/eLife.96699
  36. J Physiol. 2024 Sep 02.
    Muscle-specific mitophagy: insights into hindlimb and diaphragm responses during health and sepsis.
    Jordan D Fuqua, Paulo H C Mesquita, Michael E Taylor, Agnieszka K Borowik.
      
    Keywords:  autophagy; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287151
  37. Biochim Biophys Acta Mol Basis Dis. 2024 Sep 01. pii: S0925-4439(24)00479-4. [Epub ahead of print]1870(8): 167485
    Tcap deficiency impedes striated muscle function and heart regeneration with elevated ROS and autophagy.
    Yan Zhao, Jieling Liang, Xuan Liu, Huicong Li, Cheng Chang, Peng Gao, Fen Du, Ruilin Zhang.
      Telethonin/titin-cap (TCAP) encodes a Z-disc protein that plays important roles in sarcomere/T-tubule interactions, stretch-sensing and signaling. Mutations in TCAP are associated with muscular dystrophy and cardiomyopathy; however, the complete etiology and its roles in myocardial infarction and regeneration are not fully understood. Here, we generated tcap gene knockout zebrafish with CRISPR/Cas9 technology and observed muscular dystrophy-like phenotypes and abnormal mitochondria in skeletal muscles. The stretch-sensing ability was inhibited in tcap-/- mutants. Moreover, Tcap deficiency led to alterations in cardiac morphology and function as well as increases in reactive oxygen species (ROS) and mitophagy. In addition, the cardiac regeneration and cardiomyocyte proliferation ability of tcap-/- mutants were impaired, but these impairments could be rescued by supplementation with ROS scavengers or autophagy inhibitors. Overall, our study demonstrates the essential roles of Tcap in striated muscle function and heart regeneration. Additionally, elevations in ROS and autophagy may account for the phenotypes resulting from Tcap deficiency and could serve as novel therapeutic targets for muscular dystrophy and cardiomyopathy.
    Keywords:  Mitophagy; Muscular dystrophy; Tcap; Ventricle regeneration; Zebrafish
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167485
  38. Pharmacol Res. 2024 Aug 30. pii: S1043-6618(24)00320-7. [Epub ahead of print]208 107375
    NAFLD-associated hepatocellular carcinoma (HCC) - A compelling case for repositioning of existing mTORc1 inhibitors.
    Nutan Sharma, Lakhwinder Singh, Aditya Sharma, Ajay Kumar, Dinesh Mahajan.
      The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) is a growing concern for the high incidence rate of hepatocellular carcinoma (HCC) globally. The progression of NAFLD to HCC is heterogeneous and non-linear, involving intermediate stages of non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. There is a high unmet clinical need for appropriate diagnostic, prognostic, and therapeutic options to tackle this emerging epidemic. Unfortunately, at present, there is no validated marker to identify the risk of developing HCC in patients suffering from NAFLD or NASH. Additionally, the current treatment protocols for HCC don't differentiate between viral infection or NAFLD-specific etiology of the HCC and have a limited success rate. The mammalian target of rapamycin complex 1 (mTORc1) is an important protein involved in many vital cellular processes like lipid metabolism, glucose homeostasis, and inflammation. These cellular processes are highly implicated in NAFLD and its progression to severe liver manifestations. Additionally, hyperactivation of mTORc1 is known to promote cell proliferation, which can contribute to the genesis and progression of tumors. Many mTORc1 inhibitors are being evaluated for different types of cancers under various phases of clinical trials. This paper deliberates on the strong pathological implication of the mTORc1 signaling pathway in NAFLD and its progression to NASH and HCC and advocates for a systematic investigation of known mTORc1 inhibitors in suitable pre-clinical models of HCC having NAFLD/NASH-specific etiology.
    Keywords:  Drug repositioning; HCC; NAFLD; NASH; mTOR inhibitors
    DOI:  https://doi.org/10.1016/j.phrs.2024.107375
  39. Bioorg Med Chem Lett. 2024 Aug 30. pii: S0960-894X(24)00341-X. [Epub ahead of print] 129939
    Structure-activity relationship study of small-molecule inhibitor of Atg12-Atg3 protein-protein interaction.
    Krystof Skach, Jiri Boserle, Gal Chaim Nuta, Petra Břehová, Shani Bialik, Silvia Carvalho, Noga Kozer, Haim Barr, Ema Chaloupecká, Adi Kimchi, Radim Nencka.
      Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound 1 as an inhibitor of the ATG12-ATG3 protein-protein interaction. We focused on the systematic modification of the original hit 1, a casein kinase 2 (CK2) inhibitor, to find potent disruptors of ATG12-ATG3 protein-protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.
    Keywords:  Autophagy; Autophagy inhibition; Protein–protein interaction; Small molecule
    DOI:  https://doi.org/10.1016/j.bmcl.2024.129939
  40. Biochemistry (Mosc). 2024 Jul;89(7): 1300-1312
    Dose-Dependent Alterations of Lysosomal Activity and Alpha-Synuclein in Peripheral Blood Monocyte-Derived Macrophages and SH-SY5Y Neuroblastoma Cell Line by upon Inhibition of MTOR Protein Kinase - Assessment of the Prospects of Parkinson's Disease Therapy.
    Anastasia I Bezrukova, Katerina S Basharova, Galina V Baydakova, Ekaterina Y Zakharova, Sofya N Pchelina, Tatiana S Usenko.
      To date, the molecular mechanisms of the common neurodegenerative disorder Parkinson's disease (PD) are unknown and, as a result, there is no neuroprotective therapy that may stop or slow down the process of neuronal cell death. The aim of the current study was to evaluate the prospects of using the mTOR molecule as a potential target for PD therapy due to the dose-dependent effect of mTOR kinase activity inhibition on cellular parameters associated with, PD pathogenesis. The study used peripheral blood monocyte-derived macrophages and SH-SY5Y neuroblastoma cell line. As a result, we have for the first time showed that inhibition of mTOR by Torin1 only at a concentration of 100 nM affects the level of the lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene. Mutations in GBA1 are considered a high-risk factor for PD development. This concentration led a decrease in pathological phosphorylated alpha-synuclein (Ser129), an increase in its stable tetrameric form with no changes in the lysosomal enzyme activities and concentrations of lysosphingolipids. Our findings suggest that inhibition of the mTOR protein kinase could be a promising approach for developing therapies for PD, particularly for GBA1-associated PD.
    Keywords:  Parkinson’s disease; Torin 1; alpha-synuclein; autophagy; glucocerebrosidase; lysosomal enzyme activity; lysosphingolipids; mTOR
    DOI:  https://doi.org/10.1134/S0006297924070113
  41. IUBMB Life. 2024 Aug 30.
    Melatonin effect on breast and ovarian cancers by targeting the PI3K/Akt/mTOR pathway.
    Vahid Pourbarkhordar, Sohrab Rahmani, Ali Roohbakhsh, A Wallace Hayes, Gholamreza Karimi.
      Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), p-PI3K, Akt, p-Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl-XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin-1 phosphorylation. Beclin-1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP-activated protein kinase (AMPK), Wnt/β-catenin, mitogen-activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways.
    Keywords:  PI3K/Akt/mTOR pathway; breast cancer; melatonin; ovarian cancer
    DOI:  https://doi.org/10.1002/iub.2900
  42. Acta Pharm Sin B. 2024 Aug;14(8): 3327-3361
    Mitophagy and cGAS-STING crosstalk in neuroinflammation.
    Xiaogang Zhou, Jing Wang, Lu Yu, Gan Qiao, Dalian Qin, Betty Yuen-Kwan Law, Fang Ren, Jianming Wu, Anguo Wu.
      Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS-STING pathway, which is crucial for innate immunity. This pathway responds to mitochondrial DNA and is associated with cellular stress response. Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS-STING pathway. We critically evaluate the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions, primarily through the accumulation of damaged mitochondria, which activates the cGAS-STING pathway. This activation prompts the production of pro-inflammatory cytokines, exacerbating neuroinflammation. This review emphasizes the interaction between mitophagy and the cGAS-STING pathways. Effective mitophagy may suppress the cGAS-STING pathway, offering protection against neuroinflammation. Conversely, impaired mitophagy may activate the cGAS-STING pathway, leading to chronic neuroinflammation. Additionally, we explored how this interaction influences neurodegenerative disorders, suggesting a common mechanism underlying these diseases. In conclusion, there is a need for additional targeted research to unravel the complexities of mitophagy-cGAS-STING interactions and their role in neurodegeneration. This review highlights potential therapies targeting these pathways, potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions. This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues for neurodegenerative disease research.
    Keywords:  Crosstalk; Innate immunity; Mitochondrial DNA; Mitophagy; Neurodegenerative diseases; Neuroinflammation; Therapeutic avenues; cGAS–STING
    DOI:  https://doi.org/10.1016/j.apsb.2024.05.012
  43. Life Sci. 2024 Aug 28. pii: S0024-3205(24)00611-8. [Epub ahead of print]356 123021
    Ablation of Akt2 rescues chronic caloric restriction-provoked myocardial remodeling and dysfunction through a CDK1-mediated regulation of mitophagy.
    Min Wu, Zhao Chen, Jiade Zhu, Jie Lin, Ne N Wu, Xuefeng Han, Mengyuan Wang, Russel J Reiter, Yingmei Zhang, Yijin Wu, Jun Ren.
      Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca2+ capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca2+ governing components Na+-Ca2+ exchanger, phosphorylation of SERCA2a, mTOR (Ser2481) and ULK1 (Ser757), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser555), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner.
    Keywords:  Akt2; Cardiac; Glucocorticoids; Mitophagy; Sustained caloric restriction
    DOI:  https://doi.org/10.1016/j.lfs.2024.123021
  44. BMC Cardiovasc Disord. 2024 Aug 30. 24(1): 464
    SIRT5 induces autophagy and alleviates myocardial infarction via desuccinylation of TOM1.
    Zengliang Li, Zihe Zheng, Xiaofu Dai.
      Myocardial infarction (MI) is a prevalent form of ischemic heart disease, significantly contributing to heart disease-related deaths worldwide. This condition is primarily caused by myocardial ischemic-reperfusion injury (MIRI). Sirtuin 5 (SIRT5) is a desuccinylase known for its ability to reduce protein succinylation. Recent studies have highlighted the potential role of SIRT5 in various human diseases, including MIRI. This study aims to investigate the specific role of SIRT5 in modulating autophagy and cardiomyocyte death in a MIRI model, as well as to identify the downstream protein targets of SIRT5. Initially, we established a hypoxia/reoxygenation (H/R)-induced MIRI cell model to measure SIRT5 expression and assess its functions. Our results indicated that H/R induction led to a downregulation of SIRT5 expression, decreased autophagy, and increased cell death. Notably, overexpression of SIRT5 effectively promoted autophagy and inhibited cell death in the MIRI cell model. Mechanistically, SIRT5 was found to directly interact with the target of myb1 membrane trafficking protein (TOM1) at the K48 site, inducing its desuccinylation and stabilization. Further rescue assays revealed that TOM1 knockdown reversed the changes in autophagy and apoptosis caused by SIRT5 overexpression in the MIRI cell model. In vivo experiments demonstrated that SIRT5 alleviated myocardial injury in MI models. In conclusion, this study uncovers the role of SIRT5-mediated desuccinylation of TOM1 in regulating autophagy-related cell death in MIRI, providing new insights into potential therapeutic strategies for MI.
    Keywords:  Autophagy; Desuccinylation; MI; SIRT5; TOM1
    DOI:  https://doi.org/10.1186/s12872-024-04120-6
  45. Sci Total Environ. 2024 Aug 30. pii: S0048-9697(24)06036-4. [Epub ahead of print]952 175880
    Occupational agents-mediated asthma: From the perspective of autophagy.
    Xiu He, Dengxiang Yao, Xiaoli Yuan, Jiaqi Ban, Yuxuan Gou, Mingdan You.
      Occupational asthma (OA) is a common occupational pulmonary disease that is frequently underdiagnosed and underreported. The complexity of diagnosing and treating OA creates a significant social and economic burden, making it an important public health issue. In addition to avoiding allergens, patients with OA require pharmacotherapy; however, new therapeutic targets and strategies need further investigation. Autophagy may be a promising intervention target, but there is a lack of relevant studies summarizing the role of autophagy in OA. In this review consolidates the current understanding of OA, detailing principal and novel agents responsible for its onset. Additionally, we summarize the mechanisms of autophagy in HMW and LMW agents induced OA, revealing that occupational allergens can induce autophagy disorders in lung epithelial cells, smooth muscle cells, and dendritic cells, ultimately leading to OA through involving inflammatory responses, oxidative stress, and cell death. Finally, we discuss the prospects of targeting autophagy as an effective strategy for managing OA and even steroid-resistant asthma, encompassing autophagy interventions focused on organoids, organ-on-a-chip systems, nanomaterials vehicle, and nanobubbles; developing combined exposure models, and the role of non-classical autophagy in occupational asthma. In briefly, this review summarizes the role of autophagy in occupational asthma, offers a theoretical foundation for OA interventions based on autophagy, and identifies directions and challenges for future research.
    Keywords:  Airway hyperresponsiveness; Autophagy; High molecular weight agents; Inflammation; Low molecular weight agents; Occupational asthma; Targeted therapy
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.175880
  46. J Biol Chem. 2024 Aug 28. pii: S0021-9258(24)02229-4. [Epub ahead of print] 107728
    Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
    Juanjuan Zhang, Wenxu Li, Zhen Liu, Yingqi Chen, Xiaoyang Wei, Lu Peng, Man Xu, Yanchun Ji.
      Leber's Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G>A homoplasmic mutation damaged the highly conserved basepairing (28C-42G) in anticodon stem of tRNAThr, caused deficient t6A modification and significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr, and led to mitochondrial dysfunction. Meanwhile, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we manifested that defective nucleotide modification induced by the m.15927G>A mutation interfered with the expression of nuclear genes involved in cytoplasmic proteins essential for oxidative phosphorylation system (OXPHOS), thereby impacting the assemble and integrity of OXPHOS complexes. As a result of these mitochondrial dysfunctions, there was an imbalance in mitochondrial dynamics, particularly distinguished by an increased occurrence of mitochondrial fission. Excessive fission compromised the autophagy process, including initiation phase, formation and maturation of autophagosome. Both Parkin-mediated mitophagy and receptor-dependent mitophagy were significantly impaired in cybrids haboring the m.15927G>A mutation. These changes facilitated intrinsic apoptosis, as indicated by increased cytochrome c release and elevated levels of apoptosis-associated proteins (e.g., BAK, BAX, cleaved caspase 9, cleaved caspase 3, and cleaved PARP) in the mutant cybrids. This study demonstrates that the m.15927G>A mutation contributes to LHON by dysregulating OXPHOS biogenesis, aberrant quality control, increased autophagy, inhibited mitophagy, and abnormal apoptosis.
    Keywords:  Leber’s hereditary optic neuropathy (LHON); apoptosis; autophagy; mitochondrial tRNA(Thr) mutation; mitophagy
    DOI:  https://doi.org/10.1016/j.jbc.2024.107728
  47. Pharmacol Res. 2024 Sep 02. pii: S1043-6618(24)00339-6. [Epub ahead of print] 107394
    Investigating the Interplay between Mitophagy and Diabetic Neuropathy: Uncovering the hidden secrets of the disease pathology.
    Kiavash Hushmandi, Behzad Einollahi, Rachel Aow, Suhana Binte Suhairi, Daniel J Klionsky, Amir Reza Aref, Russel J Reiter, Pooyan Makvandi, Navid Rabiee, Yi Xu, Noushin Nabavi, Seyed Hassan Saadat, Najma Farahani, Alan Prem Kumar.
      Mitophagy, the cellular process of selectively eliminating damaged mitochondria, plays a crucial role in maintaining metabolic balance and preventing insulin resistance, both key factors in type 2 diabetes mellitus (T2DM) development. When mitophagy malfunctions in diabetic neuropathy, it triggers a cascade of metabolic disruptions, including reduced energy production, increased oxidative stress, and cell death, ultimately leading to various complications. Thus, targeting mitophagy to enhance the process may have emerged as a promising therapeutic strategy for T2DM and its complications. Notably, plant-derived compounds with β-cell protective and mitophagy-stimulating properties offer potential as novel therapeutic agents. This review highlights the intricate mechanisms linking mitophagy dysfunction to T2DM and its complications, particularly neuropathy, elucidating potential therapeutic interventions for this debilitating disease.
    Keywords:  Diabetic neuropathies; mitochondria; mitophagy; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.phrs.2024.107394
  48. Molecules. 2024 Aug 09. pii: 3773. [Epub ahead of print]29(16):
    Gaining Insight into Mitochondrial Targeting: AUTAC-Biguanide as an Anticancer Agent.
    Julie Vatté, Véronique Bourdeau, Gerardo Ferbeyre, Andreea R Schmitzer.
      AUTAC-Biguanide is a hybrid compound designed to target mitochondria, inducing their degradation by mitophagy. This study unveils the potential of biguanides as cancer cell-targeting agents, emphasizing AUTAC-Biguanide's superior antiproliferative properties compared to metformin and its selectivity for cancer cells. The mechanism behind this heightened effect includes the ability of AUTAC-Biguanide to trigger mitophagy. By providing a comprehensive analysis of these findings, this study adds valuable insights to the field of mitochondrial-targeting anticancer agents.
    Keywords:  AUATAC; autophagy; biguanide; mitochondria
    DOI:  https://doi.org/10.3390/molecules29163773
  49. Cancer Biol Ther. 2024 Dec 31. 25(1): 2398297
    TP53AIP1 induce autophagy via the AKT/mTOR signaling pathway in the breast cancer cells.
    Shutian Liu, Ting Xu, Xi Chen, Li Tang, Longjiang Li, Li Zhang, Yongqiang Yang, Jiayi Huang.
      Breast cancer ranks the first in the incidence of female cancer and is the most common cancer threatening the life and health of women worldwide.Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) is a pro-apoptotic gene downstream of p53. However, the role of TP53AIP1 in BC needs to be investigated. In vitro and in vivo experiments were conducted to assess the biological functions and associated mechanisms. Several bioinformatics analyses were made, CCK8 assay, wound healing, transwell assays, colony formation assay, EDU, flow cytometry, Immunofluorescence, qRT-PCR and Western-blotting were performed. In our study, we discovered that BC samples had low levels of TP53AIP1 expression, which correlated with a lower survival rate in BC patients. When TP53AIP1 was up-regulated, it caused a decrease in cell proliferation, migration, and invasion. It also induced epithelial-to-mesenchymal transition (EMT) and protective autophagy. Furthermore, the over-expression of TP53AIP1 suppressed tumor growth when tested in vivo. We also noticed that TP53AIP1 up-regulation resulted in decreased levels of phosphorylation in AKT and mTOR, suggesting a mechanistic role. In addition, we performed functional rescue experiments where the activation of AKT was able to counteract the impact of TP53AIP1 on the survival and autophagy in breast cancer cell lines. This suggests that TP53AIP1 acts as an oncogene by controlling the AKT/mTOR pathway. These findings reveal TP53AIP1 as a gene that suppresses tumor growth and triggers autophagy through the AKT/mTOR pathway in breast cancer cells. As a result, TP53AIP1 presents itself as a potential target for novel therapeutic approaches in treating breast cancer.
    Keywords:  TP53AIP1; autophagy; breast cancer; mTOR
    DOI:  https://doi.org/10.1080/15384047.2024.2398297
  50. bioRxiv. 2024 Aug 07. pii: 2024.08.06.606767. [Epub ahead of print]
    Episodic Transport of Protein Aggregates Achieves a Positive Size Selectivity in Aggresome Formation.
    Rui Fang, Luolan Bai, Boyan Li, Kevin Dong, Joao A Paulo, Mengying Zhou, Yi-Chi Chu, Yuyu Song, Michael Y Sherman, Steven Gygi, Christine M Field, Timothy J Mitchison, Ying Lu.
      Eukaryotic cells direct toxic misfolded proteins to various protein quality control pathways based on their chemical features and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the "aggresome," a perinuclear inclusion at the microtubule-organizing center (MTOC). However, the mechanism for selectively sequestering protein aggregates into the aggresome remains unclear. To investigate aggresome formation, we reconstituted MTOC-directed aggregate transport in Xenopus laevis egg extract using AgDD, a chemically inducible aggregation system. High-resolution single-particle tracking revealed that dynein-mediated transport of aggregates was highly episodic, with average velocity positively correlated with aggregate size. Our mechanistic model suggests that the recurrent formation of the dynein transport complex biases larger aggregates towards the active transport state, compensating for the slowdown due to viscosity. Both episodic transport and positive size selectivity are specifically associated with aggresome-dynein adaptors. Coupling conventional dynein-activating adaptors to the aggregates perturbs aggresome formation and reverses size selectivity.
    DOI:  https://doi.org/10.1101/2024.08.06.606767
  51. Immun Inflamm Dis. 2024 Sep;12(9): e70002
    Hepatocellular carcinoma and AIM2: Therapeutic potential through regulation of autophagy and macrophage polarization.
    Shuangshuang Xie, Cuiyun Wang, Xiaoyan Liu, Cheng Li, Jinhong Yu, Shumin Ma, Qiang Li, Wenjun Du.
       OBJECTIVE: Hepatocellular carcinoma (HCC) poses a significant challenge to global health. Its pathophysiology involves interconnected processes, including cell proliferation, autophagy, and macrophage polarization. However, the role of Absent in Melanoma 2 (AIM2) in HCC remains elusive.
    METHODS: The expression of AIM2 in Huh-7 and Hep3B cell lines was manipulated and cell proliferation, autophagy, apoptosis, and migration/invasion, together with the polarization of M2 macrophages, were evaluated. The markers of autophagy pathway, LC3B, Beclin-1, and P62, underwent examination through Western blot analysis. An autophagy inhibitor, 3-MA, was used to measured the role of autophagy in HCC. Finally, the effect of AIM2 overexpression on HCC was further evaluated using a subcutaneous tumor model in nude mice.
    RESULTS: Our results established that AIM2 overexpression inhibits HCC cell proliferation, migration, and invasion while promoting apoptosis and autophagy. Conversely, knockdown of AIM2 engendered opposite effects. AIM2 overexpression was correlated with reduced M2 macrophage polarization. The autophagy inhibitor substantiated AIM2's role in autophagy and identified its downstream impact on cell proliferation, migration, invasion, and macrophage polarization. In the in vivo model, overexpression of AIM2 led to the inhibition of HCC tumor growth.
    CONCLUSION: The findings underscore AIM2's crucial function in modulating major biological processes in HCC, pointing to its potential as a therapeutic target. This study inaugurally demonstrated that AIM2 activates autophagy and influences macrophage polarization, playing a role in liver cancer progression.
    Keywords:  Absent in Melanoma 2; autophagy; cell proliferation; hepatocellular carcinoma; macrophage polarization
    DOI:  https://doi.org/10.1002/iid3.70002
  52. Tissue Cell. 2024 Aug 09. pii: S0040-8166(24)00195-2. [Epub ahead of print]91 102494
    USP13 promotes acute myeloid leukemia cell proliferation and autophagy by promoting ATG5.
    Yuchu Yuan, Meizhu Xue, Feng Zhou, Lifang Gu.
       OBJECTIVE: To elucidate the role of USP13 in acute myeloid leukemia (AML) by investigating its effects on cell growth, apoptosis and autophagy, and to explore the underlying mechanisms.
    METHODS: The expression of USP13 in AML cells was assessed using quantitative PCR (qPCR) and immunoblotting. Cell Counting Kit-8 (CCK-8) and Edu staining were employed to evaluate the impact of USP13 on AML cell growth. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunostaining assays were conducted to examine the effects of USP13 on apoptosis and autophagy in AML cells, and immunoblot assays were performed to determine the potential underlying mechanistic pathway.
    RESULTS: USP13 expression was significantly elevated in AML cells, correlating with enhanced cell proliferation and resistance to apoptosis. Moreover, USP13 promoted autophagy in AML cells. Mechanistically, USP13 was found to be associated with upregulating ATG5 expression, which promoted AML progression.
    CONCLUSION: USP13 promotes AML cell growth and autophagy by upregulating ATG5.
    Keywords:  ATG5; Acute myeloid leukemia (AML); Apoptosis; Autophagy; USP13
    DOI:  https://doi.org/10.1016/j.tice.2024.102494
  53. J Biol Chem. 2024 Aug 28. pii: S0021-9258(24)02230-0. [Epub ahead of print] 107729
    Overexpression of RBM4 promotes acute myeloid leukemia cell differentiation by regulating alternative splicing of TFEB.
    Yu Duan, Sijin Liu, Jinjuan Wang, Kai Yang, Jing Xu, Qirong Wang, Jianbing Liu, Jianqing Hao, Xiaohua Cui, Yanhong Tan, Hongwei Wang, Li Li.
      Alternative splicing (AS) is an efficient and ubiquitous transcriptional regulatory mechanism that expands the coding capacity of the genome and is associated with the occurrence and progression of cancer. The differentiation-promoting regimen is a potential therapeutic approach in cancer treatment. In this study, we screened NPMc-positive and NPMc-negative AML samples from the Cancer Genome Atlas (TCGA), focusing on the splicing factor RBM4 and its splicing mechanism on the target gene TFEB, which are most relevant to the prognosis of AML. We also investigated the impact of the TFEB-dominant spliceosome on autophagy and differentiation of THP-1 and K562 cells. The results showed that RBM4 recognized the CU-rich sequence in intron 8 of TFEB, increasing the production of the TFEB-L spliceosome, which promoted autophagy. Overexpression of RBM4 increased autophagy and promoted cell differentiation. The combination of TFEB-L with the therapeutic drug rapamycin further promoted the differentiation of leukemia cell lines and primary leukemia cells in AML patients. This study suggested that overexpression of RBM4 could promote cell differentiation by promoting the production of the TFEB-dominant spliceosome, demonstrating the potential of the TFEB-dominant spliceosome combined with chemotherapy drugs to promote leukemia cell differentiation and improve patient prognosis.
    Keywords:  Acute myeloid leukemia; Alternative splicing; Autophagy; Differentiation; RBM4; TFEB
    DOI:  https://doi.org/10.1016/j.jbc.2024.107729
  54. Aging Cell. 2024 Sep 03. e14328
    Rapamycin's lifespan effect is modulated by mito-nuclear epistasis in Drosophila.
    Rita Ibrahim, Maria Bahilo Martinez, Adam J Dobson.
      The macrolide drug rapamycin is a benchmark anti-ageing drug, which robustly extends lifespan of diverse organisms. For any health intervention, it is paramount to establish whether benefits are distributed equitably among individuals and populations, and ideally to match intervention to recipients' needs. However, how responses to rapamycin vary is surprisingly understudied. Here we investigate how among-population variation in both mitochondrial and nuclear genetics shapes rapamycin's effects on lifespan. We show that epistatic "mito-nuclear" interactions, between mitochondria and nuclei, modulate the response to rapamycin treatment. Differences manifest as differential demographic effects of rapamycin, with altered age-specific mortality rate. However, a fitness cost of rapamycin early in life does not show a correlated response, suggesting that mito-nuclear epistasis can decouple costs and benefits of treatment. These findings suggest that a deeper understanding of how variation in mitochondrial and nuclear genomes shapes physiology may facilitate tailoring of anti-ageing therapy to individual need.
    Keywords:  Mito‐nuclear; drosophila; genetic variation; quantitative genetics; rapamycin
    DOI:  https://doi.org/10.1111/acel.14328
  55. Science. 2024 Aug 30. 385(6712): eadj7446
    A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.
    Sara Martin, Simone Scorzoni, Sara Cordone, Alice Mazzagatti, Galina V Beznoussenko, Amanda L Gunn, Melody Di Bona, Yonatan Eliezer, Gil Leor, Tal Ben-Yishay, Alessia Loffreda, Valeria Cancila, Maria Chiara Rainone, Marica Rosaria Ippolito, Valentino Martis, Fabio Bedin, Massimiliano Garrè, Laura Pontano Vaites, Paolo Vasapolli, Simona Polo, Dario Parazzoli, Claudio Tripodo, Alexander A Mironov, Alessandro Cuomo, Uri Ben-David, Samuel F Bakhoum, Emily M Hatch, Peter Ly, Stefano Santaguida.
      Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements. Mechanistically, proximity of micronuclei to mitochondria led to oxidation-driven homo-oligomerization of p62, limiting endosomal sorting complex required for transport (ESCRT)-dependent micronuclear envelope repair by triggering autophagic degradation. We also found that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, p62 acts as a regulator of micronuclei and may serve as a prognostic marker for tumors with high CIN.
    DOI:  https://doi.org/10.1126/science.adj7446
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