bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒01‒29
forty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex.
  2. The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.
  3. Autophagy and podocytopathy.
  4. Chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy.
  5. The mTORC1-G9a-H3K9me2 axis negatively regulates autophagy in fatty acid-induced hepatocellular lipotoxicity.
  6. The GET pathway serves to activate Atg32-mediated mitophagy by ER targeting of the Ppg1-Far complex.
  7. TORC1 phosphorylates and inhibits the ribosome preservation factor Stm1 to activate dormant ribosomes.
  8. AeiA is a novel autophagy-related protein that promotes peroxisome degradation by pexophagy in Aspergillus oryzae.
  9. Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules.
  10. Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.
  11. Cysteinyl leukotriene receptor 1 is a potent regulator of the endosomal-lysosomal system in the ARPE-19 retinal pigment epithelial cell line.
  12. Autophagy as an Anti-senescent in Aging Neurocytes.
  13. LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size.
  14. Autophagy for secretory protein: Therapeutic targets in cancer.
  15. Ufmylation reconciles salt stress-induced unfolded protein responses via ER-phagy in Arabidopsis.
  16. RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8.
  17. Autophagy in acute kidney injury and maladaptive kidney repair.
  18. Microglial autophagy in Alzheimer's disease and Parkinson's disease.
  19. Blockage of autophagosome-lysosome fusion through SNAP29 O-GlcNAcylation promotes apoptosis via ROS production.
  20. PRKN/parkin-mediated mitophagy is induced by the probiotics Saccharomyces boulardii and Lactococcus lactis.
  21. Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans.
  22. Neuroprotective effect of astragalin via activating PI3K/Akt-mTOR-mediated autophagy on APP/PS1 mice.
  23. Neuroprotective effects of melatonin-mediated mitophagy through nucleotide-binding oligomerization domain and leucine-rich repeat-containing protein X1 in neonatal hypoxic-ischemic brain damage.
  24. Ubiquitin-Mediated Regulation of Autophagy During Viral Infection.
  25. EGOC inhibits TOROID polymerization by structurally activating TORC1.
  26. Editorial: Autophagy in diseases-From basic to clinic.
  27. Southern rice black-streaked dwarf virus induces incomplete autophagy for persistence in gut epithelial cells of its vector insect.
  28. Endo-Lysosomal and Autophagy Pathway and Ubiquitin-Proteasome System in Mood Disorders: A Review Article.
  29. PTK6 inhibits autophagy to promote uveal melanoma tumorigenesis by binding to SOCS3 and regulating mTOR phosphorylation.
  30. Exosome Release Delays Senescence by Disposing of Obsolete Biomolecules.
  31. Multiple phosphorylation of the Cdc48/p97 cofactor protein Shp1/p47 occurs upon cell stress in budding yeast.
  32. Increased cysteine metabolism in PINK1 models of Parkinson's disease.
  33. Upregulation of Formaldehyde in Parkinson's Disease Found by a Near-Infrared Lysosome-Targeted Fluorescent Probe.
  34. Defective proteostasis in Alzheimer's disease.
  35. Evaluation of the Combination of Metformin and Rapamycin in an MPP+-Treated SH-SY5Y Model of Parkinson's Disease.
  36. Ribavirin extends the lifespan of Caenorhabditis elegans through AMPK-TOR Signaling.
  37. m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis.
  38. Estrogen receptor alpha mediates 17β-estradiol, up-regulates autophagy and alleviates hydrogen peroxide-induced vascular senescence.
  39. PM2.5 induces autophagy-dependent ferroptosis by endoplasmic reticulum stress in SH-SY5Y cells.
  40. Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart.
  41. The role of altered protein acetylation in neurodegenerative disease.
  42. Protein degradation: expanding the toolbox to restrain cancer drug resistance.
  43. The role of autophagy-related proteins in the pathogenesis of neuromyelitis optica spectrum disorders.
  44. Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.
  45. Multiscale imaging reveals the presence of autophagic vacuoles in developing maize endosperm.
  46. Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration.
  47. m6A reader HNRNPA2B1 destabilization of ATG4B regulates autophagic activity, proliferation and olaparib sensitivity in breast cancer.
  48. Hypoxia-Induced Autophagy Is Involved in Radioresistance via HIF1A-Associated Beclin-1 in Glioblastoma Multiforme.
  49. Metabolism, homeostasis, and aging.
  1. Nature. 2023 Jan 25.
    Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex.
    Zhicheng Cui, Gennaro Napolitano, Mariana E G de Araujo, Alessandra Esposito, Jlenia Monfregola, Lukas A Huber, Andrea Ballabio, James H Hurley.
      The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy1. The phosphorylation of TFEB by the mechanistic target of rapamycin complex 1 (mTORC1)2-5 is unique in its mTORC1 substrate recruitment mechanism, which is strictly dependent on the amino acid-mediated activation of the RagC GTPase activating protein FLCN6,7. TFEB lacks the TOR signalling motif responsible for the recruitment of other mTORC1 substrates. We used cryogenic-electron microscopy to determine the structure of TFEB as presented to mTORC1 for phosphorylation, which we refer to as the 'megacomplex'. Two full Rag-Ragulator complexes present each molecule of TFEB to the mTOR active site. One Rag-Ragulator complex is bound to Raptor in the canonical mode seen previously in the absence of TFEB. A second Rag-Ragulator complex (non-canonical) docks onto the first through a RagC GDP-dependent contact with the second Ragulator complex. The non-canonical Rag dimer binds the first helix of TFEB with a RagCGDP-dependent aspartate clamp in the cleft between the Rag G domains. In cellulo mutation of the clamp drives TFEB constitutively into the nucleus while having no effect on mTORC1 localization. The remainder of the 108-amino acid TFEB docking domain winds around Raptor and then back to RagA. The double use of RagC GDP contacts in both Rag dimers explains the strong dependence of TFEB phosphorylation on FLCN and the RagC GDP state.
    DOI:  https://doi.org/10.1038/s41586-022-05652-7
  2. Cell Rep. 2023 Jan 25. pii: S2211-1247(23)00048-7. [Epub ahead of print]42(2): 112037
    The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.
    Elizabeth R Gallagher, Erika L F Holzbaur.
      In response to lysosomal damage, cells engage several quality-control mechanisms, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy adaptor SQSTM1/p62 is recruited to damaged lysosomes in both HeLa cells and neurons and is required for lysophagic flux. The Phox and Bem1p (PB1) domain of p62 mediates oligomerization and is specifically required for lysophagy. Consistent with this observation, we find that p62 forms condensates on damaged lysosomes. These condensates are precisely tuned by the small heat shock protein HSP27, which is phosphorylated in response to lysosomal injury and maintains the liquidity of p62 condensates, facilitating autophagosome formation. Mutations in p62 have been identified in patients with amyotrophic lateral sclerosis (ALS); ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to neurodegeneration. Thus, p62 condensates regulated by HSP27 promote lysophagy by forming platforms for autophagosome biogenesis at damaged lysosomes.
    Keywords:  ALS; CP: Cell biology; CP: Neuroscience; HSP27; autophagy; condensates; lysophagy; lysosome; neurodegeneration; neurons; p62/SQSTM1; phase separation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112037
  3. Nephrol Dial Transplant. 2023 Jan 27. pii: gfad024. [Epub ahead of print]
    Autophagy and podocytopathy.
    Claudio Ponticelli, Gabriella Moroni, Francesco Reggiani.
      Autophagy is a complex process of lysosomal-dependent degradation of unwanted cellular material. In response to endogenous or exogenous stimuli, autophagy is induced and regulated by two kinases: the AMP activated kinase (AMPK) and the mammalian target of rapamycin (mTOR). Cells activated by Unc-51-like kinase 1 (ULK1) form a double membrane complex that sequesters the cargo (phagophore) and elongates producing spherical vesicles (autophagosomes). These reach and fuse with lysosomes, which degrade the cargo (autolysosomes). The resulting macromolecules are released back and recycled in the cytosol for reuse. In the podocyte, autophagy is a homeostatic mechanism that contributes to the formation and preservation of the morphological and functional integrity of actin cytoskeleton. Podocytes, fenestrated endothelial cells and glomerular basement membrane (GBM) compose the glomerular filtration barrier. Podocyte damage may cause dysfunction of the glomerular barrier, proteinuria and glomerulosclerosis in different glomerular diseases and particularly in so-called podocytopathies, namely minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Several drugs and molecules may activate autophagic function in murine models. Among them, aldosterone inhibitors, mineralocorticoid inhibitors and vitamin D3 proved to protect podocyte from injury and reduce proteinuria in clinical studies. However, no clinical trial with autophagy regulators in podocytopathies has been conducted. Caution is needed with other autophagy activators, such as mTOR inhibitors and metformin, because of potential adverse events.
    Keywords:  autophagy; focal segmental glomerulosclerosis; minimal change disease; podocytopathy; proteinuria
    DOI:  https://doi.org/10.1093/ndt/gfad024
  4. Mol Cell Biochem. 2023 Jan 25.
    Chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy.
    Yi Liu, Lan Tan, Meng-Shan Tan.
      Chaperone-mediated autophagy (CMA) is the selective degradation process of intracellular components by lysosomes, which is required for the degradation of aggregate-prone proteins and contributes to proteostasis maintenance. Proteostasis is essential for normal cell function and survival, and it is determined by the balance of protein synthesis and degradation. Because postmitotic neurons are highly susceptible to proteostasis disruption, CMA is vital for the nervous system. Since Parkinson's disease (PD) was first linked to CMA dysfunction, an increasing number of studies have shown that CMA loss, as seen during aging, occurs in the pathogenetic process of neurodegenerative diseases. Here, we review the molecular mechanisms of CMA, as well as the physiological function and regulation of this autophagy pathway. Following, we highlight its potential role in neurodegenerative diseases, and the latest advances and challenges in targeting CMA in therapy of neurodegenerative diseases.
    Keywords:  Chaperone-mediated autophagy; LAMP2A; Mechanisms; Neurodegenerative diseases; Proteostasis; Therapy
    DOI:  https://doi.org/10.1007/s11010-022-04640-9
  5. J Biol Chem. 2023 Jan 20. pii: S0021-9258(23)00069-8. [Epub ahead of print] 102937
    The mTORC1-G9a-H3K9me2 axis negatively regulates autophagy in fatty acid-induced hepatocellular lipotoxicity.
    Arjamand Mushtaq, Nissar Ul Ashraf, Mohammad Altaf.
      Defective autophagy and lipotoxicity are the hallmarks of Non-alcoholic fatty liver disease. However, the precise molecular mechanism for the defective autophagy in lipotoxic conditions is not fully known. In the current study, we elucidated that activation of the mTORC1-G9a-H3K9me2 axis in free fatty acid-induced lipotoxicity blocks autophagy by repressing key autophagy genes. The fatty acid-treated cells show mTORC1 activation, increased histone methyltransferase G9a levels, and suppressed autophagy as indicated by increased accumulation of the key autophagic cargo SQSTM1/p62 and decreased levels of autophagy-related proteins LC3II, Beclin1, and Atg7. Our Chromatin Immunoprecipitation (ChIP) analysis showed that decrease in autophagy was associated with increased levels of the G9a-mediated repressive H3K9me2 mark and decreased RNA Pol II occupancy at the promoter regions of Beclin1 and Atg7 in fatty acid-treated cells. Inhibition of mTORC1 by rapamycin in fatty acid-treated cells decreased G9a-mediated H3K9me2 occupancy and increased Pol II occupancy at Beclin1 and Atg7 promoters. Furthermore, mTORC1-inhibition increased the expression of Beclin1 and Atg7 in fatty acid-treated cells and decreased the accumulation of autophagic cargo SQSTM1/p62. Interestingly, the pharmacological inhibition of G9a alone in fatty acid-treated cells decreased the H3K9me2 mark at Atg7 and Beclin1 promoters and restored the expression of Atg7 and Beclin1. Taken together, our findings have identified the mTORC1-G9a-H3K9me2 axis as a negative regulator of the autophagy pathway in hepatocellular lipotoxicity and suggest that the G9a-mediated epigenetic repression is mechanistically a key step during the repression of autophagy in lipotoxic conditions.
    Keywords:  Autophagy; Histone methylation; Histone methyltransferase G9a; Lipotoxicity; Non-alcoholic fatty liver disease; mTORC1
    DOI:  https://doi.org/10.1016/j.jbc.2023.102937
  6. Life Sci Alliance. 2023 Apr;pii: e202201640. [Epub ahead of print]6(4):
    The GET pathway serves to activate Atg32-mediated mitophagy by ER targeting of the Ppg1-Far complex.
    Mashun Onishi, Mitsutaka Kubota, Lan Duan, Yuan Tian, Koji Okamoto.
      Mitophagy removes defective or superfluous mitochondria via selective autophagy. In yeast, the pro-mitophagic protein Atg32 localizes to the mitochondrial surface and interacts with the scaffold protein Atg11 to promote degradation of mitochondria. Although Atg32-Atg11 interactions are thought to be stabilized by Atg32 phosphorylation, how this posttranslational modification is regulated remains obscure. Here, we show that cells lacking the guided entry of the tail-anchored protein (GET) pathway exhibit reduced Atg32 phosphorylation and Atg32-Atg11 interactions, which can be rescued by additional loss of the ER-resident Ppg1-Far complex, a multi-subunit phosphatase negatively acting in mitophagy. In GET-deficient cells, Ppg1-Far is predominantly localized to mitochondria. An artificial ER anchoring of Ppg1-Far in GET-deficient cells significantly ameliorates defects in Atg32-Atg11 interactions and mitophagy. Moreover, disruption of GET and Msp1, an AAA-ATPase that extracts non-mitochondrial proteins localized to the mitochondrial surface, elicits synthetic defects in mitophagy. Collectively, we propose that the GET pathway mediates ER targeting of Ppg1-Far, thereby preventing dysregulated suppression of mitophagy activation.
    DOI:  https://doi.org/10.26508/lsa.202201640
  7. EMBO J. 2023 Jan 24. e112344
    TORC1 phosphorylates and inhibits the ribosome preservation factor Stm1 to activate dormant ribosomes.
    Sunil Shetty, Jon Hofstetter, Stefania Battaglioni, Danilo Ritz, Michael N Hall.
      Target of rapamycin complex 1 (TORC1) promotes biogenesis and inhibits the degradation of ribosomes in response to nutrient availability. To ensure a basal supply of ribosomes, cells are known to preserve a small pool of dormant ribosomes under nutrient-limited conditions. However, the regulation of these dormant ribosomes is poorly characterized. Here, we show that upon inhibition of yeast TORC1 by rapamycin or nitrogen starvation, the ribosome preservation factor Stm1 mediates the formation of nontranslating, dormant 80S ribosomes. Furthermore, Stm1-bound 80S ribosomes are protected from proteasomal degradation. Upon nutrient replenishment, TORC1 directly phosphorylates and inhibits Stm1 to reactivate translation. Finally, we find that SERBP1, a mammalian ortholog of Stm1, is likewise required for the formation of dormant 80S ribosomes upon mTORC1 inhibition in mammalian cells. These data suggest that TORC1 regulates ribosomal dormancy in an evolutionarily conserved manner by directly targeting a ribosome preservation factor.
    Keywords:  SERBP1; Stm1; TORC1; dormant ribosomes; proteasome
    DOI:  https://doi.org/10.15252/embj.2022112344
  8. FEBS Lett. 2023 Jan 26.
    AeiA is a novel autophagy-related protein that promotes peroxisome degradation by pexophagy in Aspergillus oryzae.
    Joichiro Nishio, Yoshiaki Takahashi, Masahiro Kasahara, Yoichi Takeda, Takashi Kikuma.
      Autophagy is classified into non-selective and selective autophagy, depending on the specificity of substrate degradation. In the filamentous fungus Aspergillus oryzae, selective autophagy, which includes pexophagy and mitophagy, have been observed. However, the molecular mechanism underlying selective autophagy in filamentous fungi remains unclear. Here, we identified a novel protein that interacts with the autophagy-related protein Atg8 in A. oryzae, named AoAtg8-interacting protein A (AeiA). AeiA was localized to AoAtg8-positive autophagic membrane structures and peroxisomes. Moreover, peroxisomal trafficking into the vacuole was reduced in AeiA disruptants. Taken together, AeiA is a novel selective autophagy-related protein that contributes to pexophagy in A. oryzae.
    Keywords:  Aspergillus oryzae•Pexophagy•Atg8•Autophagy•Filamentous fungi
    DOI:  https://doi.org/10.1002/1873-3468.14589
  9. Autophagy. 2023 Jan 24. 1-18
    Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules.
    Cuiwei Yang, Zhangshun Wang, Yingjin Kang, Qianqian Yi, Tong Wang, Yun Bai, Yanfen Liu.
      Eukaryotic stress granules (SGs) are highly dynamic assemblies of untranslated mRNAs and proteins that form through liquid-liquid phase separation (LLPS) under cellular stress. SG formation and elimination process is a conserved cellular strategy to promote cell survival, although the precise regulation of this process is poorly understood. Here, we screened six E3 ubiquitin ligases present in SGs and identified TRIM21 (tripartite motif containing 21) as a central regulator of SG homeostasis that is highly enriched in SGs of cells under arsenite-induced oxidative stress. Knockdown of TRIM21 promotes SG formation whereas overexpression of TRIM21 inhibits the formation of physiological and pathological SGs associated with neurodegenerative diseases. TRIM21 catalyzes K63-linked ubiquitination of the SG core protein, G3BP1 (G3BP stress granule assembly factor 1), and G3BP1 ubiquitination can effectively inhibit LLPS, in vitro. Recent reports suggested the involvement of macroautophagy/autophagy, as a stress response pathway, in the regulation of SG homeostasis. We systematically investigated well-defined autophagy receptors and identified SQSTM1/p62 (sequestosome 1) and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) as the primary receptors that directly interact with G3BP1 during arsenite-induced stress. Endogenous SQSTM1 and CALCOCO2 localize to the periphery of SGs under oxidative stress and mediate SG elimination, as single knockout of each receptor causes accumulation of physiological and pathological SGs. Collectively, our study broadens the understanding in the regulation of SG homeostasis by showing that TRIM21 and autophagy receptors modulate SG formation and elimination respectively, suggesting the possibility of clinical targeting of these molecules in therapeutic strategies for neurodegenerative diseases.Abbreviations: ACTB: actin beta; ALS: amyotrophic lateral sclerosis; BafA1: bafilomycin A1; BECN1: beclin 1; C9orf72: C9orf72-SMCR8 complex subunit; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; FTD: frontotemporal dementia; FUS: FUS RNA binding protein; G3BP1: G3BP stress granule assembly factor 1; GFP: green fluorescent protein; LLPS: liquid-liquid phase separation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NBR1: NBR1 autophagy cargo receptor; NES: nuclear export signal; OPTN: optineurin; RFP: red fluorescent protein; SQSTM1/p62: sequestosome 1; SG: stress granule; TAX1BP1: Tax1 binding protein 1; TOLLIP: toll interacting protein; TRIM21: tripartite motif containing 21; TRIM56: tripartite motif containing 56; UB: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.
    Keywords:  Autophagy receptor; CALCOCO2; G3BP1; SQSTM1; TRIM21; stress granule; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2164427
  10. Autophagy. 2023 Jan 24.
    Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.
    Ayesha Sen, Julia Boix, David Pla-Martín.
      Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them towards elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.
    Keywords:  - mitophagy; endosomes; mtDNA
    DOI:  https://doi.org/10.1080/15548627.2023.2170959
  11. Traffic. 2023 Jan 27.
    Cysteinyl leukotriene receptor 1 is a potent regulator of the endosomal-lysosomal system in the ARPE-19 retinal pigment epithelial cell line.
    Andreas Koller, Susanne Maria Brunner, Julia Preishuber-Pflügl, Christian Runge, Anja-Maria Ladek, Herbert Anton Reitsamer, Andrea Trost.
      The endosomal-lysosomal system is central for cell homeostasis and comprises the functions and dynamics of particular organelles including endosomes, lysosomes and autophagosomes. In previous studies, we found that the cysteinyl leukotriene receptor 1 (CysLTR1) regulates autophagy in the retinal pigment epithelial cell line ARPE-19 under basal cellular conditions. However, the underlying mechanism by which CysLTR1 regulates autophagy is unknown. Thus, in the present study, the effects of CysLTR1 inhibition on the endosomal-lysosomal system are analyzed in detail to identify the role of CysLTR1 in cell homeostasis and autophagy regulation. CysLTR1 inhibition in ARPE-19 cells by Zafirlukast, a CysLTR1 antagonist, depleted the lysosomal pool. Furthermore, CysLTR1 antagonization reduced endocytic capacity and internalization of epidermal growth factor and decreased levels of the transferrin receptor, CD71. Serum starvation abolished the effect of Zafirlukast on the autophagic flux, which identifies the endocytic regulation of serum components by CysLTR1 as an important autophagy-modulating mechanism. The role of CysLTR1 in inflammation and cell stress has been exceedingly studied, but its involvement in the endosomal-lysosomal pathway is largely unknown. This current study provides new insights into basal activity of CysLTR1 on cellular endocytosis and the subsequent impact on downstream processes like autophagy. This article is protected by copyright. All rights reserved.
    Keywords:  CysLTR1; EGF endocytosis; Zafirlukast; autophagy; endosomal-lysosomal system; retinal pigment epithelial cells
    DOI:  https://doi.org/10.1111/tra.12881
  12. Curr Mol Med. 2023 Jan 20.
    Autophagy as an Anti-senescent in Aging Neurocytes.
    Basheer Abdullah Marzoog.
      Neuron homeostasis is crucial for the organism, and its maintenance is multifactorial, including autophagy. The turnover of aberrant intracellular components is a fundamental pathogenetic mechanism for cell aging. Autophagy is involved in the acceleration of the neurocyte aging process and the modification of cell longevity. Neurocyte aging is a process of loss of cell identity through cellular and subcellular changes that include molecular loss of epigenetics, transcriptomic, proteomic, and autophagy dysfunction. Autophagy dysfunction is the hallmark of neurocyte aging. Cell aging is the credential feature of neurodegenerative diseases. Pathophysiologically, aged neurocytes are characterized by dysregulated autophagy and subsequently neurocyte metabolic stress, resulting in accelerated neurocyte aging. In particular, chaperone-mediated autophagy perturbation results in upregulated expression of aging and apoptosis genes. Aged neurocytes are also characterized by the down-regulation of autophagy-related genes, such as ATG5-ATG12, LC3-II / LC3-I ratio, Beclin-1, and p62. Slowing aging through autophagy targeting is sufficient to improve prognosis in neurodegenerative diseases. Three primary anti-senescent molecules are involved in the aging process: mTOR, AMPK, and Sirtuins. Autophagy therapeutic effects can be applied to reverse and slow aging. This article discusses current advances in the role of autophagy in neurocyte homeostasis, aging, and potential therapeutic strategies to reduce aging and increase cell longevity.
    Keywords:  Aging; Autophagy; Differentiation; Homeostasis; Longevity; Neurocyte; Reprogramming; Transdifferentiation
    DOI:  https://doi.org/10.2174/1566524023666230120102718
  13. Cell Mol Life Sci. 2023 Jan 28. 80(2): 53
    LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size.
    Jenny Serra-Vinardell, Maxwell B Sandler, Raffaella De Pace, Javier Manzella-Lapeira, Antony Cougnoux, Keyvan Keyvanfar, Wendy J Introne, Joseph A Brzostowski, Michael E Ward, William A Gahl, Prashant Sharma, May Christine C Malicdan.
      Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients' induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype.
    Keywords:  Autolysosome tubule; Autolysosomes; Chediak–Higashi syndrome; Lysosome fission; Protolysosomes; iPSC
    DOI:  https://doi.org/10.1007/s00018-023-04695-x
  14. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(22)00088-8. [Epub ahead of print]133 159-180
    Autophagy for secretory protein: Therapeutic targets in cancer.
    Kewal Kumar Mahapatra, Srimanta Patra, Soumya Ranjan Mishra, Bishnu Prasad Behera, Shankargouda Patil, Sujit Kumar Bhutia.
      Autophagy, a classical cellular degradative catabolic process, also involves a functionally discrete non-degradative role in eukaryotic cells. It imparts critical regulatory function on conventional and unconventional protein secretion (degradative and secretory autophagy with distinct lysosomal degradation and extracellular expulsion, respectively) pathways. The N-amino terminal leader sequence containing proteins follows a conventional secretion pathway, while the leader-less proteins opt for secretory autophagy. The secretory autophagic process ensembles core autophagy machinery proteins, specifically ULK1/2, Beclin 1, LC3, and GABARAP, in coordination with Golgi re-assembly and stacking proteins (GRASPs). The secretory omegasomes fuse with the plasma membrane for the expulsion of cytosolic cargos to the extracellular environment. Alternatively, the secretory omegasomes also fuse with multi-vesicular bodies (MVBs) and harmonize ESCRTs (Complex I; TSG101) and Rab GTPase for their release to extracellular space. Autophagy has been associated with the secretion of diverse proteins involved in cellular signaling, inflammation, and carcinogenesis. Secreted proteins play an essential role in cancer by sustaining cell proliferation, inhibiting apoptosis, enhancing angiogenesis and metastasis, immune cell regulation, modulation of cellular energy metabolism, and resistance to anticancer drugs. The complexity of autophagy regulation during tumorigenesis is dependent on protein secretion pathways. Autophagy-regulated TOR-autophagy spatial coupling compartment complex energizes enhanced secretion of pro-inflammatory cytokines and leaderless proteins such as HMGB1. In conclusion, the chapter reviews the role of autophagy in regulating conventional and unconventional protein secretion pathways and its possible role in cancer.
    Keywords:  Autophagy; Cancer; Protein secretion; Unconventional autophagy
    DOI:  https://doi.org/10.1016/bs.apcsb.2022.10.009
  15. Proc Natl Acad Sci U S A. 2023 Jan 31. 120(5): e2208351120
    Ufmylation reconciles salt stress-induced unfolded protein responses via ER-phagy in Arabidopsis.
    Baiying Li, Fangfang Niu, Yonglun Zeng, Man Kei Tse, Cesi Deng, Liu Hong, Shengyu Gao, Sze Wan Lo, Wenhan Cao, Shuxian Huang, Yasin Dagdas, Liwen Jiang.
      In plants, the endomembrane system is tightly regulated in response to environmental stresses for maintaining cellular homeostasis. Autophagosomes, the double membrane organelles forming upon nutrient deprivation or stress induction, degrade bulky cytosolic materials for nutrient turnover. Though abiotic stresses have been reported to induce plant autophagy, few receptors or regulators for selective autophagy have been characterized for specific stresses. Here, we have applied immunoprecipitation followed by tandem mass spectrometry using the autophagosome marker protein ATG8 as bait and have identified the E3 ligase of the ufmylation system Ufl1 as a bona fide ATG8 interactor under salt stress. Notably, core components in the ufmylation cascade, Ufl1 and Ufm1, interact with the autophagy kinase complexes proteins ATG1 and ATG6. Cellular and genetic analysis showed that Ufl1 is important for endoplasmic reticulum (ER)-phagy under persisting salt stress. Loss-of-function mutants of Ufl1 display a salt stress hypersensitive phenotype and abnormal ER morphology. Prolonged ER stress responses are detected in ufl1 mutants that phenocopy the autophagy dysfunction atg5 mutants. Consistently, expression of ufmylation cascade components is up-regulated by salt stress. Taken together, our study demonstrates the role of ufmylation in regulating ER homeostasis under salt stress through ER-phagy.
    DOI:  https://doi.org/10.1073/pnas.2208351120
  16. Sci Adv. 2023 Jan 25. 9(4): eadd6097
    RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8.
    Takayuki Imanishi, Midori Unno, Natsumi Yoneda, Yasutaka Motomura, Miho Mochizuki, Takaharu Sasaki, Manolis Pasparakis, Takashi Saito.
      Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation. Here, we show that T cell-specific RIPK1 deficiency in mice leads to the premature senescence of T cells and induces various age-related diseases, resulting in premature death. RIPK1 deficiency causes higher basal activation of mTORC1 (mechanistic target of rapamycin complex 1) that drives enhanced cytokine production, induction of senescence-related genes, and increased activation of caspase-3/7, which are restored by inhibition of mTORC1. Critically, normal aged T cells exhibit similar phenotypes and responses. Mechanistically, a combined deficiency of RIPK3 and caspase-8 inhibition restores the impaired proliferative responses; the elevated activation of Akt, mTORC1, extracellular signal-regulated kinase, and caspase-3/7; and the increased expression of senescence-related genes in RIPK1-deficient CD4 T cells. Last, we revealed that the senescent phenotype of RIPK1-deficient and aged CD4 T cells is restored in the normal tissue environment. Thus, we have clarified the function of RIPK3 and caspase-8 in inducing CD4 T cell senescence, which is modulated by environmental signals.
    DOI:  https://doi.org/10.1126/sciadv.add6097
  17. Burns Trauma. 2023 ;11 tkac059
    Autophagy in acute kidney injury and maladaptive kidney repair.
    Yu Xiang, Ying Fu, Wenwen Wu, Chengyuan Tang, Zheng Dong.
      Acute kidney injury (AKI) is a major renal disease characterized by a sudden decrease in kidney function. After AKI, the kidney has the ability to repair, but if the initial injury is severe the repair may be incomplete or maladaptive and result in chronic kidney problems. Autophagy is a highly conserved pathway to deliver intracellular contents to lysosomes for degradation. Autophagy plays an important role in maintaining renal function and is involved in the pathogenesis of renal diseases. Autophagy is activated in various forms of AKI and acts as a defense mechanism against kidney cell injury and death. After AKI, autophagy is maintained at a relatively high level in kidney tubule cells during maladaptive kidney repair but the role of autophagy in maladaptive kidney repair has been controversial. Nonetheless, recent studies have demonstrated that autophagy may contribute to maladaptive kidney repair after AKI by inducing tubular degeneration and promoting a profibrotic phenotype in renal tubule cells. In this review, we analyze the role and regulation of autophagy in kidney injury and repair and discuss the therapeutic strategies by targeting autophagy.
    Keywords:  Acute kidney injury; Autophagy; Chronic kidney disease; Fibrosis; Maladaptive repair
    DOI:  https://doi.org/10.1093/burnst/tkac059
  18. Front Aging Neurosci. 2022 ;14 1065183
    Microglial autophagy in Alzheimer's disease and Parkinson's disease.
    Zhifu Wang, Qi Wang, Shihua Li, Xiao-Jiang Li, Weili Yang, Dajian He.
      Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases, characterized by gradual and selective loss of neurons in the central nervous system. They affect more than 50 million people worldwide, and their incidence increases with age. Although most cases of AD and PD are sporadic, some are caused by genetic mutations that are inherited. Both sporadic and familial cases display complex neuropathology and represent the most perplexing neurological disorders. Because of the undefined pathogenesis and complex clinical manifestations, there is still no effective treatment for both AD and PD. Understanding the pathogenesis of these important neurodegenerative diseases is important for developing successful therapies. Increasing evidence suggests that microglial autophagy is associated with the pathogenesis of AD and PD, and its dysfunction has been implicated in disease progression. In this review, we focus on the autophagy function in microglia and its dysfunction in AD and PD disease models in an attempt to help our understanding of the pathogenesis and identifying new therapeutic targets of AD and PD.
    Keywords:  AD; PD; autophagy; microglia; neurodegeneration
    DOI:  https://doi.org/10.3389/fnagi.2022.1065183
  19. Autophagy. 2023 Jan 27.
    Blockage of autophagosome-lysosome fusion through SNAP29 O-GlcNAcylation promotes apoptosis via ROS production.
    Francesca Romana Pellegrini, Sara De Martino, Giulia Fianco, Irene Ventura, Davide Valente, Mario Fiore, Daniela Trisciuoglio, Francesca Degrassi.
      Macroautophagy/autophagy has been shown to exert a dual role in cancer i.e., promoting cell survival or cell death depending on the cellular context and the cancer stage. Therefore, development of potent autophagy modulators, with a clear mechanistic understanding of their target action, has paramount importance in both mechanistic and clinical studies. In the process of exploring the mechanism of action of a previously identified cytotoxic small molecule (SM15) designed to target microtubules and the interaction domain of microtubules and the kinetochore component NDC80/HEC1, we discovered that the molecule acts as a potent autophagy inhibitor. By using several biochemical and cell biology assays we demonstrated that SM15 blocks basal autophagic flux by inhibiting the fusion of correctly formed autophagosomes with lysosomes. SM15-induced autophagic flux blockage promoted apoptosis-mediated cell death associated with ROS production. Interestingly, autophagic flux blockage, apoptosis induction and ROS production were rescued by genetic or pharmacological inhibition of OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) or by expressing an O-GlcNAcylation-defective mutant of the SNARE fusion complex component SNAP29, pointing to SNAP29 as the molecular target of SM15 in autophagy. Accordingly, SM15 was found to enhance SNAP29 O-GlcNAcylation and, thereby, inhibit the formation of the SNARE fusion complex. In conclusion, these findings identify a new pathway in autophagy connecting O-GlcNAcylated SNAP29 to autophagic flux blockage and autophagosome accumulation, that, in turn, drives ROS production and apoptotic cell death. Consequently, modulation of SNAP29 activity may represent a new opportunity for therapeutic intervention in cancer and other autophagy-associated diseases.
    Keywords:  O-GlcNAcylation; SNAP29; anticancer therapy; apoptosis; autophagic flux; autophagy; kinetochore; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2023.2170962
  20. Autophagy. 2023 Jan 28.
    PRKN/parkin-mediated mitophagy is induced by the probiotics Saccharomyces boulardii and Lactococcus lactis.
    Peter John Hawrysh, Jinghua Gao, Stephanie Tan, Amy Oh, Justin Nodwell, Thomas A Tompkins, G Angus McQuibban.
      Mitochondrial impairment is a hallmark feature of neurodegenerative disorders, such as Parkinson disease, and PRKN/parkin-mediated mitophagy serves to remove unhealthy mitochondria from cells. Notably, probiotics are used to alleviate several symptoms of Parkinson disease including impaired locomotion and neurodegeneration in preclinical studies and constipation in clinical trials. There is some evidence to suggest that probiotics can modulate mitochondrial quality control pathways. In this study, we screened 49 probiotic strains and tested distinct stages of mitophagy to determine whether probiotic treatment could upregulate mitophagy in cells undergoing mitochondrial stress. We found two probiotics, Saccharomyces boulardii and Lactococcus lactis, that upregulated mitochondrial PRKN recruitment, phospho-ubiquitination, and MFN degradation in our cellular assays. Administration of these strains to Drosophila that were exposed to paraquat, a mitochondrial toxin, resulted in improved longevity and motor function. Further, we directly observed increased lysosomal degradation of dysfunctional mitochondria in the treated Drosophila brains. These effects were replicated in vitro and in vivo with supra-physiological concentrations of exogenous soluble factors that are released by probiotics in cultures grown under laboratory conditions. We identified methyl-isoquinoline-6-carboxylate as one candidate molecule, which upregulates mitochondrial PRKN recruitment, phospho-ubiquitination, MFN degradation, and lysosomal degradation of damaged mitochondria. Addition of methyl-isoquinoline-6-carboxylate to the fly food restored motor function to paraquat-treated Drosophila. These data suggest a novel mechanism that is facilitated by probiotics to stimulate mitophagy through a PRKN-dependent pathway, which could explain the potential therapeutic benefit of probiotic administration to patients with Parkinson disease.
    Keywords:  Drosophila; PRKN/parkin; Parkinson disease; melanoxadin; methyl-isoquinoline-6-carboxylate; mitochondria; picolinic acid
    DOI:  https://doi.org/10.1080/15548627.2023.2172873
  21. Front Genet. 2022 ;13 1012706
    Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans.
    Nicholas Schultheis, Robert Becker, Gelila Berhanu, Alexander Kapral, Matthew Roseman, Shalini Shah, Alyssa Connell, Scott Selleck.
      Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer's disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.
    Keywords:  autophagy; co-receptors; heparan sulfate; lipid metabolism; mitochondria; nicastrin; presenilin; proteoglycans
    DOI:  https://doi.org/10.3389/fgene.2022.1012706
  22. Cell Death Discov. 2023 Jan 21. 9(1): 15
    Neuroprotective effect of astragalin via activating PI3K/Akt-mTOR-mediated autophagy on APP/PS1 mice.
    Cui-Zhu Yang, Shu-Han Wang, Run-Heng Zhang, Jia-Hong Lin, Ying-Hong Tian, Ya-Qi Yang, Jing Liu, Yu-Xin Ma.
      As a small molecule flavonoid, astragalin (AST) has anti-inflammatory, anti-cancer, and anti-oxidation effects. However, the impact and molecular mechanism of AST in Alzheimer's disease (AD) are still not clear. This study aims to investigate the neuroprotective effect and mechanism of AST on APP/PS1 mice and Aβ25-35-injured HT22 cells. In this study, we found that AST ameliorated cognitive dysfunction, reduced hippocampal neuronal damage and loss, and Aβ pathology in APP/PS1 mice. Subsequently, AST activated autophagy and up-regulated the levels of autophagic flux-related protein in APP/PS1 mice and Aβ25-35-induced injury in HT22 cells. Interestingly, AST down-regulated the phosphorylation level of PI3K/Akt-mTOR pathway-related proteins, which was reversed by autophagy inhibitors 3-Methyladenine (3-MA) or Bafilomycin A1 (Baf A1). At the same time, consistent with the impacts of Akt inhibitor MK2206 and mTOR inhibitor rapamycin, inhibited levels of autophagy in Aβ25-35-injured HT22 cells were activated by the administration of AST. Taken together, these results suggested that AST played key neuroprotective roles on AD via stimulating PI3K/Akt-mTOR pathway-mediated autophagy and autophagic flux. This study revealed a new mechanism of autophagy regulation behind the neuroprotection impact of AST for AD treatment.
    DOI:  https://doi.org/10.1038/s41420-023-01324-1
  23. FASEB J. 2023 Feb;37(2): e22784
    Neuroprotective effects of melatonin-mediated mitophagy through nucleotide-binding oligomerization domain and leucine-rich repeat-containing protein X1 in neonatal hypoxic-ischemic brain damage.
    Yi Zhang, Dan Chen, Yiwei Wang, Xingzao Wang, Zhong Zhang, Ying Xin.
      Hypoxia-ischemia (HI) is a major cause of brain damage in neonates. Mitochondrial dysfunction acts as a hub for a broad spectrum of signaling events, culminating in cell death triggered by HI. A neuroprotective role of melatonin (MT) has been proposed, and mitophagy regulation seems to be important for cell survival. However, the molecular mechanisms underlying MT-mediated mitophagy during HI treatment are poorly defined. Nucleotide-binding oligomerization domain and leucine-rich repeat-containing protein X1 (NLRX1) has emerged as a critical regulator of mitochondrial dynamics and neuronal death that participates in the pathology of diverse diseases. This study aimed to clarify whether NLRX1 participates in the regulation of mitophagy during MT treatment for hypoxic-ischemic brain damage (HIBD). We demonstrated that MT protected neonates from HIBD through NLRX1-mediated mitophagy in vitro and in vivo. Meanwhile, MT upregulated the expression of NLRX1, Beclin-1, and autophagy-related 7 (ATG7) but decreased the expression of the mammalian target of rapamycin (mTOR) and translocase of the inner membrane of mitochondrion 23 (TIM23). Moreover, the neuroprotective effects of MT were abolished by silencing NLRX1 after oxygen-glucose deprivation (OGD). In addition, the downregulation of mTOR and upregulation of Beclin-1 and ATG7 by MT were inhibited after silencing NLRX1 under OGD. In summary, MT modulates mitophagy induction through NLRX1 and plays a protective role in HIBD, providing insight into potential therapeutic targets for MT to exert neuroprotection.
    Keywords:  NLRX1; apoptosis; brain damage; hypoxia-ischemia; melatonin; mitophagy; neonates; neuroprotective
    DOI:  https://doi.org/10.1096/fj.202201523R
  24. Curr Clin Microbiol Rep. 2023 Jan 13. 1-8
    Ubiquitin-Mediated Regulation of Autophagy During Viral Infection.
    Joydeep Nag, Janvi Patel, Shashank Tripathi.
      Purpose of Review: Virus infections skew the host autophagic response to meet their replication and transmission demands by tapping into the critical host regulatory mechanisms that control the autophagic flux. This review is a compendium of previous reports highlighting the mechanisms that viruses adapt to hijack the host ubiquitination machinery to repurpose autophagy for their sustenance.Recent Findings: Emerging evidence suggests a critical role of host ubiquitin machinery in the manifestation of the antiviral or proviral functions of autophagy. Lately, more emphasis has been laid to identify specific host E3 ubiquitin ligases, their targets (viral or host), and characterizing corresponding ubiquitin linkages by biochemical or genome-wide genetic screening approaches.
    Summary: Here, we highlight how viruses ingeniously engage and subvert the host ubiquitin-autophagy system to promote virus replication and antagonize intracellular innate immune responses.
    Keywords:  Autophagy; Innate immunity; Interferon; Proteasome; Ubiquitin; Virus
    DOI:  https://doi.org/10.1007/s40588-022-00186-y
  25. Nat Struct Mol Biol. 2023 Jan 26.
    EGOC inhibits TOROID polymerization by structurally activating TORC1.
    Manoël Prouteau, Clélia Bourgoint, Jan Felix, Lenny Bonadei, Yashar Sadian, Caroline Gabus, Savvas N Savvides, Irina Gutsche, Ambroise Desfosses, Robbie Loewith.
      Target of rapamycin complex 1 (TORC1) is a protein kinase controlling cell homeostasis and growth in response to nutrients and stresses. In Saccharomyces cerevisiae, glucose depletion triggers a redistribution of TORC1 from a dispersed localization over the vacuole surface into a large, inactive condensate called TOROID (TORC1 organized in inhibited domains). However, the mechanisms governing this transition have been unclear. Here, we show that acute depletion and repletion of EGO complex (EGOC) activity is sufficient to control TOROID distribution, independently of other nutrient-signaling pathways. The 3.9-Å-resolution structure of TORC1 from TOROID cryo-EM data together with interrogation of key interactions in vivo provide structural insights into TORC1-TORC1' and TORC1-EGOC interaction interfaces. These data support a model in which glucose-dependent activation of EGOC triggers binding to TORC1 at an interface required for TOROID assembly, preventing TORC1 polymerization and promoting release of active TORC1.
    DOI:  https://doi.org/10.1038/s41594-022-00912-6
  26. Front Physiol. 2022 ;13 1115511
    Editorial: Autophagy in diseases-From basic to clinic.
    Jie Yang, Zhenhong Ni, Huifeng Pi, Adam Bohnert, Zhiqiang Deng.
      
    Keywords:  autophagy; autophagy regulation; autophagy-related clinical practice; autophagy-related diseases; cardiovascular diseases; diabetes; protozoa
    DOI:  https://doi.org/10.3389/fphys.2022.1115511
  27. PLoS Pathog. 2023 Jan 27. 19(1): e1011134
    Southern rice black-streaked dwarf virus induces incomplete autophagy for persistence in gut epithelial cells of its vector insect.
    Lu Zhang, Wenwen Liu, Nan Wu, Hui Wang, Zhongkai Zhang, Yule Liu, Xifeng Wang.
      Autophagy plays an important role in virus infection of the host, because viral components and particles can be degraded by the host's autophagy and some viruses may be able to hijack and subvert autophagy for its benefit. However, details on the mechanisms that govern autophagy for immunity against viral infections or benefit viral survival remain largely unknown. Plant reoviruses such as southern rice black-streaked dwarf virus (SRBSDV), which seriously threaten crop yield, are only transmitted by vector insects. Here, we report a novel mechanism by which SRBSDV induces incomplete autophagy by blocking autophagosome-lysosome fusion, resulting in viral accumulation in gut epithelial cells of its vector, white-backed planthopper (Sogatella furcifera). SRBSDV infection leads to stimulation of the c-Jun N-terminal kinase (JNK) signaling pathway, which further activates autophagy. Mature and assembling virions were found close to the edge7 of the outer membrane of autophagosomes. Inhibition autophagy leads to the decrease of autophagosomes, which resulting in impaired maturation of virions and the decrease of virus titer, whereas activation of autophagy facilitated virus titer. Further, SRBSDV inhibited fusion of autophagosomes and lysosomes by interacting with lysosomal-associated membrane protein 1 (LAMP1) using viral P10. Thus, SRBSDV not only avoids being degrading by lysosomes, but also further hijacks these non-fusing autophagosomes for its subsistence. Our findings reveal a novel mechanism of reovirus persistence, which can explain why SRBSDV can be acquired and transmitted rapidly by its insect vector.
    DOI:  https://doi.org/10.1371/journal.ppat.1011134
  28. Neuropsychiatr Dis Treat. 2023 ;19 133-151
    Endo-Lysosomal and Autophagy Pathway and Ubiquitin-Proteasome System in Mood Disorders: A Review Article.
    Petala Matutino Santos, Giovanna Pereira Campos, Camila Nascimento.
      Mood disorders are disabling conditions that cause significant functional impairment. Due to the clinical heterogeneity and complex nature of these disorders, diagnostic and treatment strategies face challenges. The etiology of mood disorders is multifactorial, involving genetic and environmental aspects that are associated with specific biological pathways including inflammation, oxidative stress, and neuroprotection. Alterations in these pathways may reduce the cell's ability to recover from stress conditions occurring during mood episodes. The endo-lysosomal and autophagy pathway (ELAP) and the ubiquitin-proteasome system (UPS) play critical roles in protein homeostasis, impacting neuroplasticity and neurodevelopment. Thus, emerging evidence has suggested a role for these pathways in mental disorders. In the case of neurodegenerative diseases (NDDs), a deeper understanding in the role of ELAP and UPS has been critical to discover new treatment targets. Since it is suggested that NDDs and mood disorders share clinical symptomatology and risk factors, it has been hypothesized that there might be common underlying molecular pathways. Here, we review the importance of the ELAP and UPS for the central nervous system and for mood disorders. Finally, we discuss potential translational strategies for the diagnosis and treatment of major depressive disorder and bipolar disorder associated with these pathways.
    Keywords:  autophagy; endo-lysosomal pathway; endo-lysosome; mood disorders; neuroplasticity; novel treatments; translational science; treatment target; ubiquitin-proteasome system
    DOI:  https://doi.org/10.2147/NDT.S376380
  29. Cell Death Dis. 2023 Jan 23. 14(1): 55
    PTK6 inhibits autophagy to promote uveal melanoma tumorigenesis by binding to SOCS3 and regulating mTOR phosphorylation.
    Bo Liu, Xueting Yao, Chaoyang Zhang, Yufen Liu, Li Wei, Qinying Huang, Mengting Wang, Yanchen Zhang, Danning Hu, Wencan Wu.
      Autophagy dysfunction is one of the common causes of tumor formation and plays an important role in uveal melanoma (UM). However, little is known about the regulatory mechanisms of autophagy in UM. Here, we show that PTK6 can promote the proliferation, migration, and invasion of UM cells by inhibiting autophagy. SOCS3 can inhibit the proliferation, migration, and invasion of UM cells. Overexpression of SOCS3 can partially rescue the PTK6-induced promotion of UM cell proliferation, migration, and invasion. Mechanistically, PTK6 can bind to SOCS3, and SOCS3 can downregulate the expression of PTK6. Furthermore, PTK6 can upregulate the phosphorylation of mTOR to inhibit autophagy. Taken together, our findings demonstrate the functions of PTK6 and SOCS3 in UM cells and targeting the SOCS3-PTK6 signaling axis might be a novel and promising therapeutic strategy for patients with UM.
    DOI:  https://doi.org/10.1038/s41419-023-05590-w
  30. Adv Sci (Weinh). 2023 Jan 22. e2204826
    Exosome Release Delays Senescence by Disposing of Obsolete Biomolecules.
    Wenchong Zou, Mingqiang Lai, Yuanjun Jiang, Linlin Mao, Wu Zhou, Sheng Zhang, Pinglin Lai, Bin Guo, Tiantian Wei, Chengtao Nie, Lei Zheng, Jiahuan Zhang, Xuefei Gao, Xiaoyang Zhao, Laixin Xia, Zhipeng Zou, Anling Liu, Shiming Liu, Zhong-Kai Cui, Xiaochun Bai.
      Accumulation of obsolete biomolecules can accelerate cell senescence and organism aging. The two efficient intracellular systems, namely the ubiquitin-proteasome system and the autophagy-lysosome system, play important roles in dealing with cellular wastes. However, how multicellular organisms orchestrate the processing of obsolete molecules and delay aging remains unclear. Herein, it is shown that prevention of exosome release by GW4869 or Rab27a-/- accelerated senescence in various cells and mice, while stimulating exosome release by nutrient restriction delays aging. Interestingly, exosomes isolate from serum-deprived cells or diet-restricted human plasma, enriched with garbage biomolecules, including misfolded proteins, oxidized lipids, and proteins. These cellular wastes can be englobed by macrophages, eventually, for disintegration in vivo. Inhibition of nutrient-sensing mTORC1 signaling increases exosome release and delays senescence, while constitutive activation of mTORC1 reduces exosome secretion and exacerbates senescence in vitro and in mice. Notably, inhibition of exosome release attenuates nutrient restriction- or rapamycin-delayed senescence, supporting a key role for exosome secretion in this process. This study reveals a potential mechanism by which stimulated exosome release delays aging in multicellular organisms, by orchestrating the harmful biomolecules disposal via exosomes and macrophages.
    Keywords:  aging; exosomes; mTORC1; nutrient restriction; obsolete biomolecules
    DOI:  https://doi.org/10.1002/advs.202204826
  31. Life Sci Alliance. 2023 Apr;pii: e202201642. [Epub ahead of print]6(4):
    Multiple phosphorylation of the Cdc48/p97 cofactor protein Shp1/p47 occurs upon cell stress in budding yeast.
    Alexander Agrotis, Frederic Lamoliatte, Thomas D Williams, Ailsa Black, Rhuari Horberry, Adrien Rousseau.
      The homohexameric p97 complex, composed of Cdc48 subunits in yeast, is a crucial component of protein quality control pathways including ER-associated degradation. The complex acts to segregate protein complexes in an ATP-dependent manner, requiring the engagement of cofactor proteins that determine substrate specificity. The function of different Cdc48 cofactors and how they are regulated remains relatively poorly understood. In this study, we assess the phosphorylation of Cdc48 adaptor proteins, revealing a unique and distinctive phosphorylation pattern of Shp1/p47 that changed in response to TORC1 inhibition. Site-directed mutagenesis confirmed that this pattern corresponded to phosphorylation at residues S108 and S315 of Shp1, with the double-phosphorylated form becoming predominant upon TORC1 inhibition, ER-stress, and oxidative stress. Finally, we assessed candidate kinases and phosphatases responsible for Shp1 phosphorylation and identified two regulators. We found that cells lacking the kinase Mpk1/Slt2 show reduced Shp1 phosphorylation, whereas impaired PP1 phosphatase catalytic subunit (Glc7) activity resulted in increased Shp1 phosphorylation. Overall, these findings identify a phosphoregulation of Shp1 at multiple sites by Mpk1 kinase and PP1 phosphatase upon various stresses.
    DOI:  https://doi.org/10.26508/lsa.202201642
  32. Dis Model Mech. 2023 Jan 01. pii: dmm049727. [Epub ahead of print]16(1):
    Increased cysteine metabolism in PINK1 models of Parkinson's disease.
    Marco Travaglio, Filippos Michopoulos, Yizhou Yu, Rebeka Popovic, Edmund Foster, Muireann Coen, L Miguel Martins.
      Parkinson's disease (PD), an age-dependent neurodegenerative disease, is characterised by the selective loss of dopaminergic neurons in the substantia nigra (SN). Mitochondrial dysfunction is a hallmark of PD, and mutations in PINK1, a gene necessary for mitochondrial fitness, cause PD. Drosophila melanogaster flies with pink1 mutations exhibit mitochondrial defects and dopaminergic cell loss and are used as a PD model. To gain an integrated view of the cellular changes caused by defects in the PINK1 pathway of mitochondrial quality control, we combined metabolomics and transcriptomics analysis in pink1-mutant flies with human induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) with a PINK1 mutation. We observed alterations in cysteine metabolism in both the fly and human PD models. Mitochondrial dysfunction in the NPCs resulted in changes in several metabolites that are linked to cysteine synthesis and increased glutathione levels. We conclude that alterations in cysteine metabolism may compensate for increased oxidative stress in PD, revealing a unifying mechanism of early-stage PD pathology that may be targeted for drug development. This article has an associated First Person interview with the first author of the paper.
    Keywords:   Drosophila ; Metabolism; Mitochondria; PINK1; Parkinson's disease; Stem cell research
    DOI:  https://doi.org/10.1242/dmm.049727
  33. Anal Chem. 2023 Jan 23.
    Upregulation of Formaldehyde in Parkinson's Disease Found by a Near-Infrared Lysosome-Targeted Fluorescent Probe.
    Wei Quan, Guihua Zhang, Yanxia Li, Wenhui Song, Jingting Zhan, Weiying Lin.
      Parkinson's disease (PD) is one of the major neurodegenerative diseases caused by complex pathological processes. As a signal molecule, formaldehyde is closely linked to nervous systems, but the relationship between PD and formaldehyde levels remains largely unclear. We speculated that formaldehyde might be a potential biomarker for PD. To prove it, we constructed the first near-infrared (NIR) lysosome-targeted formaldehyde fluorescent probe (named NIR-Lyso-FA) to explore the relationship between formaldehyde and PD. The novel fluorescent probe achieves formaldehyde detection in vitro and in vivo, thanks to its excellent properties such as NIR emission, large Stokes shift, and fast response to formaldehyde. Crucially, utilizing the novel probe NIR-Lyso-FA, formaldehyde overexpression was discovered for the first time in cellular, zebrafish, and mouse PD models, supporting our guess that formaldehyde can function as a possible biomarker for PD. We anticipate that this finding will offer insightful information for PD pathophysiology, diagnosis, medication development, and treatment.
    DOI:  https://doi.org/10.1021/acs.analchem.2c04567
  34. Ageing Res Rev. 2023 Jan 21. pii: S1568-1637(23)00021-1. [Epub ahead of print]85 101862
    Defective proteostasis in Alzheimer's disease.
    Danielle Cozachenco, Felipe C Ribeiro, Sergio T Ferreira.
      The homeostasis of cellular proteins, or proteostasis, is critical for neuronal function and for brain processes, including learning and memory. Increasing evidence indicates that defective proteostasis contributes to the progression of neurodegenerative disorders, including Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. Proteostasis comprises a set of cellular mechanisms that control protein synthesis, folding, post-translational modification and degradation, all of which are deregulated in AD. Importantly, deregulation of proteostasis plays a key role in synapse dysfunction and in memory impairment, the major clinical manifestation of AD. Here, we discuss molecular pathways involved in protein synthesis and degradation that are altered in AD, and possible pharmacological approaches to correct these defects.
    Keywords:  Alzheimer’s disease; Amyloid-β oligomers; Autophagy; Degradation; ER stress; Protein synthesis; Proteostasis; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.arr.2023.101862
  35. Adv Pharmacol Pharm Sci. 2023 ;2023 3830861
    Evaluation of the Combination of Metformin and Rapamycin in an MPP+-Treated SH-SY5Y Model of Parkinson's Disease.
    Chureerat Norradee, Kawinthra Khwanraj, Tatcha Balit, Permphan Dharmasaroja.
      Metformin (MET) and rapamycin (RAPA) have been reported to protect against neurodegeneration in cellular and animal models of Parkinson's disease (PD). MET, which is a first-line drug for type 2 diabetes, and RAPA are known as mTORC1 inhibitors. MET also acts as an AMPK activator, which leads to the inhibition of mTORC1 activity. mTORC1 is a downstream target of Akt signaling. Inactivation of Akt/mTORC1 and its downstream S6K1 can promote autophagy, a process involved in PD pathogenesis. Based on their mechanisms and potential benefits, we evaluated the potential protective effect of pretreatment with combinations of MET and RAPA in a 1-methyl-4-phenylpyridinium ion (MPP+)-treated SH-SY5Y neuronal cell model of PD. The results showed that MET and RAPA combinations lowered cell viability after exposure to MPP+. Increased LC3-II levels by MPP+ were not altered by MET and RAPA pretreatment. In normal neuronal cells, MET and RAPA pretreatment inhibited the phosphorylation of both Akt and S6K1, and the phosphorylation remained suppressed after MPP+ exposure. These findings suggest that when cells were exposed to MPP+, suppressed phosphorylation of both Akt and S6K1 by the MET and RAPA combination may lead to an inappropriate autophagic response, resulting in increased cell death.
    DOI:  https://doi.org/10.1155/2023/3830861
  36. Eur J Pharmacol. 2023 Jan 24. pii: S0014-2999(23)00059-6. [Epub ahead of print] 175548
    Ribavirin extends the lifespan of Caenorhabditis elegans through AMPK-TOR Signaling.
    Ganlan Zhang, Hui Liu, Ting Xue, Xiangming Kong, Dongmei Tian, Libo Luo, Yanhua Yang, Keqing Xu, Youheng Wei, Ziheng Zhuang.
      Aging is a process accompanied by widespread degenerative changes which are a major cause of human disease and disability. One goal of aging research is to develop interventions or drugs that can extend organism lifespan and treat age-related diseases. Here, we report the identification of a broad spectrum anti-viral agent, ribavirin, as a potential pharmacological aging intervention. Ribavirin extended the lifespan and healthspan of Caenorhabditis elegans by inhibiting Target of Rapamycin (TOR) signaling and activating AMP-activated protein kinase (AMPK). Moreover, our data indicate that ribavirin activated AMPK by reducing the levels of adenosine triphosphate (ATP) and lysosomal v-ATPase-Ragulator-AXIN Complex. Thus, our studies successfully identify ribavirin as a potential anti-aging drug, and indicate that its anti-aging effect is mediated via AMPK-TOR signaling.
    Keywords:  AMPK; Aging; Caenorhabditis elegans; Lifespan; Ribavirin; TOR
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175548
  37. Front Immunol. 2022 ;13 1094556
    m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis.
    Youjing Yang, Qianmin Li, Yi Ling, Linxin Leng, Yu Ma, Lian Xue, Guoyuan Lu, Yue Ding, Jianzhong Li, Shasha Tao.
      The dysregulation of autophagy contributes to renal fibrosis. N6-Methyladenosine (m6A) RNA modification is a critical mediator of autophagy. Our previous studies have reported that the disorder of the PPARα/fatty acid oxidation (FAO) axis in renal tubular cells is suppressed by STAT6, which is involved in the regulation of renal fibrotic processes. Here, we found that canagliflozin significantly upregulates SQSTM1/P62, promoting PPARα-mediated FAO by inducing autophagy-dependent STAT6 degradation both in TGF-β1-treated HK2 cells and in unilateral ureteral occlusion (UUO) and ischemia-reperfusion (I/R) renal fibrosis mouse models. Knockdown of P62/SQSTM1 led to the impairment autophagic flux and the dysregulation of the STAT6/PPARα axis, which was confirmed by SQSTM1/P62cKO mice with UUO treatment along with bioinformatics analysis. Furthermore, SQSTM1/P62 deficiency in renal tubular cells inhibited canagliflozin's effects that prevent FAO disorder in renal tubular cells and renal fibrosis. Mechanistically, the level of m6A eraser FTO, which interacted with SQSTM1 mRNA, decreased in the renal tubular cells both in vitro and in vivo after canagliflozin administration. Decrease in FTO stabilized SQSTM1 mRNA, which induced autophagosome formation. Collectively, this study uncovered a previously unrecognized function of canagliflozin in FTO in the autophagy modulation through the regulation of SQSTM1 mRNA stability in the renal tubular STAT6/PPARα/FAO axis and renal fibrosis.
    Keywords:  N6-methyladenosine; SQSTM1; STAT6; autophagy; canagliflozin; renal fibrosis
    DOI:  https://doi.org/10.3389/fimmu.2022.1094556
  38. Biogerontology. 2023 Jan 23.
    Estrogen receptor alpha mediates 17β-estradiol, up-regulates autophagy and alleviates hydrogen peroxide-induced vascular senescence.
    Xiuting Xiang, LiangZhen Xie, Jieqi Lin, Rahmawati Pare, Guanshen Huang, Jianming Huang, Yuyan Wang, Shicong Song, Yunjun Ruan.
      Atherosclerosis threatens human health by developing cardiovascular diseases, the deadliest disease world widely. The major mechanism contributing to the formation of atherosclerosis is mainly due to vascular endothelial cell (VECs) senescence. We have shown that 17β-estradiol (17β-E2) may protect VECs from senescence by upregulating autophagy. However, little is known about how 17β-E2 activates the autophagy pathway to alleviate cellular senescence. Therefore, the aim of this study is to determine the role of estrogen receptor (ER) α and β in the effects of 17β-E2 on vascular autophagy and aging through in vitro and in vivo models. Hydrogen peroxide (H2O2) was used to establish Human Umbilical Vein Endothelial Cells (HUVECs) senescence. Autophagy activity was measured through immunofluorescence and immunohistochemistry staining of light chain 3 (LC3) expression. Inhibition of ER activity was established using shRNA gene silencing and ER antagonist. Compared with ER-β knockdown, we found that knockdown of ER-α resulted in a significant increase in the extent of HUVEC senescence and senescence-associated secretory phenotype (SASP) secretion. ER-α-specific shRNA was found to reduce 17β-E2-induced autophagy, promote HUVEC senescence, disrupt the morphology of HUVECs, and increase the expression of Rb dephosphorylation and SASP. These in vitro findings were found consistent with the in vivo results. In conclusion, our data suggest that 17β-E2 activates the activity of ER-α and then increases the formation of autophagosomes (LC3 high expression) and decreases the fusion of lysosomes with autophagic vesicles (P62 low expression), which in turn serves to decrease the secretion of SASP caused by H2O2 and consequently inhibit H2O2-induced senescence in HUVEC cells.
    Keywords:  17β-Estradiol; Autophagy; Estrogen receptor alpha; Estrogen receptor beta; Redox signaling; Senescence
    DOI:  https://doi.org/10.1007/s10522-023-10015-4
  39. J Appl Toxicol. 2023 Jan 26.
    PM2.5 induces autophagy-dependent ferroptosis by endoplasmic reticulum stress in SH-SY5Y cells.
    Can Can Guo, Zhao Meng Xu, Yi Lyu, Xiao Hui Li, Zhao Fei Li, Hui He, Feng Jie Tian, Jin Ping Zheng.
      PM2.5 has been a global environmental problem threatening public health in recent years. PM2.5 exposure was associated with an increased risk of neurodegenerative diseases related to neuronal apoptosis. Ferroptosis is a non-apoptotic form of programmed the cell death, characterized by excess iron-dependent lipid peroxidation products. Whether PM2.5 could induce ferroptosis in cells and thus be involved in its neurotoxicity is unknown. In this study, we found that PM2.5 induced endoplasmic reticulum stress, apoptosis, autophagy, and ferroptosis in neuroblastoma SH-SY5Y cells. Interestingly, ferroptosis was the predominant form of mortality in the presence of high doses of PM2.5 exposure. In addition, the endoplasmic reticulum stress inhibitor 4-PBA inhibited PM2.5 -induced cellular autophagy, apoptosis, and ferroptosis. Autophagy inhibitors CQ alleviated PM2.5 -induced ferroptosis but did not reverse apoptosis. We also found that inhibition of both endoplasmic reticulum stress and autophagy reversed the PM2.5 -induced increase in the expression level of cytophagy NCOA4. Our results suggested that PM2.5 -induced ferroptosis in SH-SY5Y cells was autophagy-dependent ferroptosis due to endoplasmic reticulum stress, which might be associated with the elevation of iron content caused by NCOA4-mediated ferritin autophagy.
    Keywords:  Autophagy; Endoplasmic reticulum stress; Ferroptosis; PM2.5; SH-SY5Y cells
    DOI:  https://doi.org/10.1002/jat.4439
  40. Physiol Rep. 2023 Jan;11(2): e15574
    Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart.
    Ana Victoria Rojo-García, Mathias Vanmunster, Alexander Pacolet, Frank Suhr.
      Sedentary behavior has become ingrained in our society and has been linked to cardiovascular diseases. Physical inactivity is the main characteristic of sedentary behavior. However, its impact on cardiovascular disease is not clear. Therefore, we investigated the effect of physical inactivity in an established mouse model on gene clusters associated with cardiac fibrosis, electrophysiology, cell regeneration, and tissue degradation/turnover. We investigated a sedentary group (CTR, n = 10) versus a tail suspension group (TS, n = 11) that caused hindlimb unloading and consequently physical inactivity. Through histological, protein content, and transcript analysis approaches, we found that cardiac fibrosis-related genes partly change, with significant TS-associated increases in Tgfb1, but without changes in Col1a1 and Fn1. These changes are not translated into fibrosis at tissue level. We further detected TS-mediated increases in protein degradation- (Trim63, p < 0.001; Fbxo32, p = 0.0947 as well as in biosynthesis-related [P70s6kb1, p < 0.01]). Corroborating these results, we found increased expression of autophagy markers such as Atg7 (p < 0.01) and ULK1 (p < 0.05). Two cardiomyocyte regeneration- and sarcomerogenesis-related genes, Yap (p = 0.0535) and Srf (p < 0.001), increased upon TS compared to CTR conditions. Finally, we found significant upregulation of Gja1 (p < 0.05) and a significant downregulation of Aqp1 (p < 0.05). Our data demonstrate that merely 2 weeks of reduced physical activity induce changes in genes associated with cardiac structure and electrophysiology. Hence, these data should find the basis for novel research directed to evaluate the interplay of cardiac functioning and physical inactivity.
    Keywords:  cardiomyocytes; heart; mouse; physical inactivity; tail suspension
    DOI:  https://doi.org/10.14814/phy2.15574
  41. Front Aging Neurosci. 2022 ;14 1025473
    The role of altered protein acetylation in neurodegenerative disease.
    Fariha Kabir, Rachel Atkinson, Anthony L Cook, Andrew James Phipps, Anna Elizabeth King.
      Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.
    Keywords:  HATs; HDACs; PTMs; acetylation; cytoskeleton; neurodegenerative disease; proteostasis
    DOI:  https://doi.org/10.3389/fnagi.2022.1025473
  42. J Hematol Oncol. 2023 Jan 24. 16(1): 6
    Protein degradation: expanding the toolbox to restrain cancer drug resistance.
    Hui Ming, Bowen Li, Jingwen Jiang, Siyuan Qin, Edouard C Nice, Weifeng He, Tingyuan Lang, Canhua Huang.
      Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.
    Keywords:  Chaperone-mediated autophagy; DUBs; Drug resistance; E3 ligase; Protein degradation
    DOI:  https://doi.org/10.1186/s13045-023-01398-5
  43. Bioengineered. 2022 Jun;13(6): 14329-14338
    The role of autophagy-related proteins in the pathogenesis of neuromyelitis optica spectrum disorders.
    Hong-Liang Guo, Xiao-Ran Shen, Xiao-Ting Liang, Ling-Zhou Li.
      This study aimed to investigate the expression of autophagy-related proteins in a mouse model of neuromyelitis optica (NMO). Mice were assigned to one of four groups: an animal experimental model group (NMO-EAE group, given with exogenous IL-17A), Interleukin-17 monoclonal antibody intervention group (NMO-EAE_0IL17inb), No exogenous interleukin-17 enhanced immune intervention group (NMO-EAE_0IL17), and a control group. Behavioral scores were assessed in each group, and the protein expressions of sequestosome 1 (P62), Beclin-1, the mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K-I), and LC3II/LC3I were detected using Western blotting. In the NMO-EAE_0IL17 group, the expression of Beclin-1 decreased, the LC3II/LC3I ratio was lower, and the expressions of P62, mTOR, and PI3K-I increased; after administration of IL-17A inhibitor into the brain tissue, however, the expression of Beclin-1 increased significantly, along with the LC3II/LC3I ratio, while the expressions of P62, mTOR and PI3K-I protein decreased significantly. In terms of behavioral scores, the scores of optic neuritis and myelitis were more serious, onset occurred earlier and the progress was faster, after the administration of IL-17A. In the mechanism of NMO animal model, IL-17A may regulate autophagy and affect the disease process through the activation of the PI3K-mTOR signaling pathway.
    Keywords:  Neuromyelitis optica; animal model; autophagy; signaling pathway
    DOI:  https://doi.org/10.1080/21655979.2022.2084273
  44. Cell Death Dis. 2023 Jan 26. 14(1): 61
    Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.
    Vrushank Bhatt, Taijin Lan, Wenping Wang, Jerry Kong, Eduardo Cararo Lopes, Jianming Wang, Khoosheh Khayati, Akash Raju, Michael Rangel, Enrique Lopez, Zhixian Sherrie Hu, Xuefei Luo, Xiaoyang Su, Jyoti Malhotra, Wenwei Hu, Sharon R Pine, Eileen White, Jessie Yanxiang Guo.
      LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.
    DOI:  https://doi.org/10.1038/s41419-023-05592-8
  45. Front Plant Sci. 2022 ;13 1082890
    Multiscale imaging reveals the presence of autophagic vacuoles in developing maize endosperm.
    Elsa Arcalís, Ulrike Hörmann-Dietrich, Eva Stöger.
      Cereal endosperm is solely devoted to the storage of proteins and starch that will be used by the embryo upon germination. The high degree of specialization of this tissue is reflected in its endomembrane system, in which ER derived protein bodies and protein storage vacuoles (PSVs) are of particular interest. In maize seeds, the main storage proteins are zeins, that form transport incompetent aggregates within the ER lumen and finally build protein bodies that bud from the ER. In contrast to the zeins, the maize globulins are not very abundant and the vacuolar storage compartment of maize endosperm is not fully described. Whereas in other cereals, including wheat and barley, the PSV serves as the main protein storage compartment, only small, globulin-containing PSVs have been identified in maize so far. We present here a multi-scale set of data, ranging from live-cell imaging to more sophisticated 3D electron microscopy techniques (SBF-SEM), that has allowed us to investigate in detail the vacuoles in maize endosperm cells, including a novel, autophagic vacuole that is present in early developmental stages.
    Keywords:  autophagy; lytic vacuole; maize endosperm; multiscale imaging; storage vacuole
    DOI:  https://doi.org/10.3389/fpls.2022.1082890
  46. PLoS One. 2023 ;18(1): e0262792
    Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration.
    Shreyasi Chatterjee, Megan Sealey, Eva Ruiz, Chrysia M Pegasiou, Keeley Brookes, Sam Green, Anna Crisford, Michael Duque-Vasquez, Emma Luckett, Rebecca Robertson, Philippa Richardson, Girish Vajramani, Paul Grundy, Diederik Bulters, Christopher Proud, Mariana Vargas-Caballero, Amritpal Mudher.
      Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.
    DOI:  https://doi.org/10.1371/journal.pone.0262792
  47. Exp Cell Res. 2023 Jan 21. pii: S0014-4827(23)00034-4. [Epub ahead of print] 113487
    m6A reader HNRNPA2B1 destabilization of ATG4B regulates autophagic activity, proliferation and olaparib sensitivity in breast cancer.
    Renjing Zheng, Yuanhang Yu, Lianqiu Lv, Yue Zhang, Huifang Deng, Jiyong Li, Bo Zhang.
      N6-methyladenosine RNA (m6A) is the most extensive epigenetic modification in mRNA and influences tumor progression. However, the role of m6A regulators and specific mechanisms in breast cancer still need further study. Here, we investigated the significance of the m6A reader HNRNPA2B1 and explored its influence on autophagy and drug sensitivity in breast cancer. HNRNPA2B1 was selected by bioinformatics analysis, and its high expression level was identified in breast cancer tissues and cell lines. HNRNPA2B1 was related to poor prognosis. Downregulation of HNRNPA2B1 reduced proliferation, enhanced autophagic flux, and partially reversed de novo resistance to olaparib in breast cancer. ATG4B was determined by RIP and MeRIP assays as a downstream gene of HNRNPA2B1, by which recognized the m6A site in the 3'UTR. Overexpression of ATG4B rescued the malignancy driven by HNRNPA2B1 in breast cancer cells and increased the olaparib sensitivity. Our study revealed that the m6A reader HNRNPA2B1 mediated proliferation and autophagy in breast cancer cell lines by facilitating ATG4B mRNA decay and targeting HNRNPA2B1/m6A/ATG4B might enhance the olaparib sensitivity of breast cancer cells.
    Keywords:  Autophagy; Breast cancer; HNRNPA2B1; N(6)-methyladenosine RNA; Olaparib
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113487
  48. Heliyon. 2023 Jan;9(1): e12820
    Hypoxia-Induced Autophagy Is Involved in Radioresistance via HIF1A-Associated Beclin-1 in Glioblastoma Multiforme.
    Jielin Wei, Kuikui Zhu, Zhe Yang, Ying Zhou, Zihan Xia, Jinghua Ren, Yanxia Zhao, Gang Wu, Cuiwei Liu.
      Radioresistance is the major factor of glioblastoma multiforme (GBM) treatment failure and relapse. Hypoxia and autophagy are linked to radioresistance and poor prognosis in solid tumors, but mechanisms remain unknown. Thus, we hypothesize that hypoxia may activate autophagy through two critical factors, HIF1A and Beclin-1, resulting in radioresistance of GBM in vitro and in vivo. In this study, we first demonstrated that HIF1A was overexpressed in GBM tissues and predicted a poor prognosis via bioinformatics. Secondly, we determined that hypoxia induced high expression of HIF1A and upregulated levels of Beclin-1 and autophagy, while HIF1A knockdown by shRNA reduced the expression of Beclin-1. Then we revealed the crosstalk and mechanisms of HIF1A-associated-Beclin-1 in three aspects: (a) transcriptional regulation, (b) protein interaction, and (c) HIF1A/BNIP3/Beclin-1 signaling pathway. Furthermore, we confirmed that silencing HIF1A enhanced the radiosensitivity of GBM in vitro and in vivo. Additionally, Beclin-1 suppression by 3-MA could reverse radioresistance induced by HIF1A under hypoxia. In conclusion, we demonstrated that hypoxia triggered autophagy via HIF1A-associated Beclin-1, resulting in radioresistance in GBM. HIF1A knockdown improved GBM radiosensitivity, and silencing Beclin-1 could reverse HIF1A-induced radioresistance under hypoxic conditions. These findings may help us comprehend the molecular underpinnings of hypoxia-induced autophagy and provide a novel perspective and prospective treatment for GBM radiosensitization.
    Keywords:  Autophagy; Beclin-1; Hypoxia; Hypoxia-inducible factor 1 alpha (HIF1A); Radiotherapy
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e12820
  49. Trends Endocrinol Metab. 2023 Jan 19. pii: S1043-2760(23)00014-0. [Epub ahead of print]
    Metabolism, homeostasis, and aging.
    Alibek Moldakozhayev, Vadim N Gladyshev.
      We propose a two-mode (pursuit/maintenance) model of metabolism defined by usable resource availability. Pursuit, consisting of anabolism and catabolism, dominates when usable resources are plentiful and leads to the generation of metabolic waste. In turn, maintenance of a system is activated by elevated metabolic waste during resource depletion. Interaction with the environment results in pendulum-like swings between these metabolic states in thriveless attempts to maintain the least deleterious organismal state - ephemeral homeostasis. Imperfectness of biological processes during these attempts supports the accumulation of the deleteriome, driving organismal aging. We discuss how metabolic adjustment by the environment and resource stabilization may modulate healthspan and lifespan.
    Keywords:  aging; homeostasis; maintenance; metabolism; pursuit
    DOI:  https://doi.org/10.1016/j.tem.2023.01.003
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