bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2021–04–18
43 papers selected by
Viktor Korolchuk, Newcastle University
  1. Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.
  2. Phosphorylation of the LIR domain of SCOC modulates ATG8 binding affinity and specificity.
  3. mTOR as a senescence manipulation target: A forked road.
  4. Upregulated SOCC and IP3R calcium channels and subsequent elevated cytoplasmic calcium signaling promote nonalcoholic fatty liver disease by inhibiting autophagy.
  5. Autophagy and senescence, converging roles in pathophysiology as seen through mouse models.
  6. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.
  7. p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control.
  8. Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish.
  9. Autophagic Heterogeneity in Gastric Adenocarcinoma.
  10. Autophagy in the diabetic heart: A potential pharmacotherapeutic target in diabetic cardiomyopathy.
  11. Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington's disease.
  12. A Web of Science-based scientometric analysis about mammalian target of rapamycin signaling pathway in kidney disease from 1986 to 2020.
  13. A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage.
  14. WDR45, one gene associated with multiple neurodevelopmental disorders.
  15. Lysosome (Dys)function in Atherosclerosis-A Big Weight on the Shoulders of a Small Organelle.
  16. The roles of the inhibitory autophagy regulator Rubicon in the heart: A new therapeutic target to prevent cardiac cell death.
  17. A functional outside-in signaling network of proteoglycans and matrix molecules regulating autophagy.
  18. A model for a partnership of lipid transfer proteins and scramblases in membrane expansion and organelle biogenesis.
  19. Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.
  20. Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors.
  21. Role and mechanisms of autophagy in lung metabolism and repair.
  22. A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells.
  23. Interorganelle communication, aging, and neurodegeneration.
  24. Comment on "mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC".
  25. The role of autophagy in escaping therapy-induced polyploidy/senescence.
  26. Autophagy and senescence: Insights from normal and cancer stem cells.
  27. The dynamic mechanism of 4E-BP1 recognition and phosphorylation by mTORC1.
  28. Autophagy of the m6A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis.
  29. The Role of Autophagy in Skeletal Muscle Diseases.
  30. Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells.
  31. Making Insulin and Staying Out of Autoimmune Trouble: The Beta-Cell Conundrum.
  32. Autophagy and PTEN in DNA damage-induced senescence.
  33. Nlp promotes autophagy through facilitating the interaction of Rab7 and FYCO1.
  34. Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity.
  35. Kog1/Raptor mediates metabolic rewiring during nutrient limitation by controlling SNF1/AMPK activity.
  36. mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif.
  37. 3D quantification of autophagy activation and autophagosome-to-mitochondria recruitment in a Drosophila model of Parkinson's disease.
  38. Zinc‑finger E‑box‑binding homeobox 1 alleviates acute kidney injury by activating autophagy and the AMPK/mTOR pathway.
  39. NIPSNAP protein family emerges as a sensor of mitochondrial health.
  40. Fisetin inhibits inflammation and induces autophagy by mediating PI3K/AKT/mTOR signaling in LPS-induced RAW264.7 cells.
  41. Roles of FAM134B in diseases from the perspectives of organelle membrane morphogenesis and cellular homeostasis.
  42. Organelle degradation in the lens by PLAAT phospholipases.
  43. Autophagy and senescence in cancer therapy.
  1. J Cell Biol. 2021 Jun 07. pii: e202006043. [Epub ahead of print]220(6):
    Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.
    Yumiko Oshima, Etienne Cartier, Liron Boyman, Nicolas Verhoeven, Brian M Polster, Weiliang Huang, Maureen Kane, W Jonathan Lederer, Mariusz Karbowski.
      Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell ("mosaic distribution"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.
    DOI:  https://doi.org/10.1083/jcb.202006043
  2. J Mol Biol. 2021 Apr 09. pii: S0022-2836(21)00188-1. [Epub ahead of print] 166987
    Phosphorylation of the LIR domain of SCOC modulates ATG8 binding affinity and specificity.
    Martina Wirth, Stephane Mouilleron, Wenxin Zhang, Eva Sjottem, Yakubu Princely Abudu, Ashish Jain, Hallvard Lauritz Olsvik, Jack-Ansgar Bruun, Minoo Razi, Harold B J Jefferies, Rebecca Lee, Dhira Joshi, Nicola O'Reilly, Terje Johansen, Sharon A Tooze.
      Autophagy is a highly conserved degradative pathway, essential for cellular homeostasis and implicated in diseases including cancer and neurodegeneration. Autophagy-related 8 (ATG8) proteins play a central role in autophagosome formation and selective delivery of cytoplasmic cargo to lysosomes by recruiting autophagy adaptors and receptors. The LC3-interacting region (LIR) docking site (LDS) of ATG8 proteins binds to LIR motifs present in autophagy adaptors and receptors. LIR-ATG8 interactions can be highly selective for specific mammalian ATG8 family members (LC3A-C, GABARAP, and GABARAPL1-2) and how this specificity is generated and regulated is incompletely understood. We have identified a LIR motif in the Golgi protein SCOC (short coiled-coil protein) exhibiting strong binding to GABARAP, GABARAPL1, LC3A and LC3C. The residues within and surrounding the core LIR motif of the SCOC LIR domain were phosphorylated by autophagy-related kinases (ULK1-3, TBK1) increasing specifically LC3 family binding. More distant flanking residues also contributed to ATG8 binding. Loss of these residues was compensated by phosphorylation of serine residues immediately adjacent to the core LIR motif, indicating that the interactions of the flanking LIR regions with the LDS are important and highly dynamic. Our comprehensive structural, biophysical and biochemical analyses support and provide novel mechanistic insights into how phosphorylation of LIR domain residues regulates the affinity and binding specificity of ATG8 proteins towards autophagy adaptors and receptors.
    Keywords:  Autophagy; Bio-layer interferometry; LIR motif; crystal structure; phosphorylation
    DOI:  https://doi.org/10.1016/j.jmb.2021.166987
  3. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00018-X. [Epub ahead of print]150 335-363
    mTOR as a senescence manipulation target: A forked road.
    Sarah Saoudaoui, Monique Bernard, Guillaume B Cardin, Nicolas Malaquin, Apostolos Christopoulos, Francis Rodier.
      Cellular senescence, cancer and aging are highly interconnected. Among many important molecular machines that lie at the intersection of this triad, the mechanistic (formerly mammalian) target of rapamycin (mTOR) is a central regulator of cell metabolism, proliferation, and survival. The mTOR signaling cascade is essential to maintain cellular homeostasis in normal biological processes or in response to stress, and its dysregulation is implicated in the progression of many disorders, including age-associated diseases. Accordingly, the pharmacological implications of mTOR inhibition using rapamycin or others rapalogs span the treatment of various human diseases from immune disorders to cancer. Importantly, rapamycin is one of the only known pan-species drugs that can extend lifespan. The molecular and cellular mechanisms explaining the phenotypic consequences of mTOR are vast and heavily studied. In this review, we will focus on the potential role of mTOR in the context of cellular senescence, a tumor suppressor mechanism and a pillar of aging. We will explore the link between senescence, autophagy and mTOR and discuss the opportunities to exploit senescence-associated mTOR functions to manipulate senescence phenotypes in age-associated diseases and cancer treatment.
    Keywords:  Aging; Apoptosis; Autophagy; Lifespan; Metabolism; Senescence; Senolytics; mTOR
    DOI:  https://doi.org/10.1016/bs.acr.2021.02.002
  4. Mol Cell Biochem. 2021 Apr 17.
    Upregulated SOCC and IP3R calcium channels and subsequent elevated cytoplasmic calcium signaling promote nonalcoholic fatty liver disease by inhibiting autophagy.
    Lin Zhang, Yifan Zhang, Yuanqing Jiang, Xiaobing Dou, Songtao Li, Hui Chai, Qianyu Qian, Miaojuan Wang.
      Nonalcoholic fatty liver disease (NAFLD) is related to elevated cytoplasmic calcium signaling in hepatocytes, which may be mediated by store-operated calcium channel (SOCC) and inositol triphosphate receptor (IP3R). However, the regulatory effect of calcium signaling on lipid accumulation and degeneration in hepatocytes and the underlying molecular mechanism remain unknown. Autophagy inhibition promotes lipid accumulation and steatosis in hepatocytes. However, the association between elevated calcium signaling and autophagy inhibition in hepatocytes and its effect on hepatocyte fatty lesions remain unclear. Here, we established a mouse hepatocyte fatty gradient model using oleic acid. SOCC and IP3R channel opening and cytoplasmic calcium levels gradually increased with the hepatocyte pimelosis degree, whereas autophagy gradually decreased. We also established an optimal oleic acid (OOA) hepatocyte model, observing significantly increased SOCC and IP3R channel opening and calcium influx alongside significantly decreased autophagy and aggravated cellular fatty lesion. Calcium channel blockers (CCBs) and calcium channel gene silencing reagents (CCGSRs), respectively, reversed these effects, indicating that elevated cytoplasmic calcium signaling promotes NAFLD occurrence and the development by inhibiting hepatocyte autophagy. In the OOA model, upregulated extracellular regulated protein kinases 1/2 (ERK1/2), which can be regulated by SOCC and IP3R proteins transient receptor potential canonical 1 (TRPC1)/IP3R with elevated cytoplasmic calcium signaling, over-inhibited forkhead/winged helix O (FOXO) signaling and over-activated mammalian target of rapamycin complex 1 (mTORC1) signaling. Over-inhibited FOXO signaling significantly downregulated autophagy-related gene 12, which inhibits autophagosome maturation, while over-activated mTORC1 signaling over-inactivated Unc-51 like autophagy activating kinase 1, which inhibits preautophagosome formation. CCBs and CCGSRs recovered autophagy by significantly downregulating ERK1/2 to block abnormal changes in FOXO and mTORC1 signaling. Our findings indicate that upregulated SOCC and IP3R channels and subsequent elevated cytoplasmic calcium signaling in hepatocyte fatty lesions inhibits hepatocyte autophagy through (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways, causes lipid accumulation and degeneration in hepatocytes, and promotes NAFLD occurrence and development.
    Keywords:  (TRPC1/IP3R)/ERK/(FOXO/MTORC1) signaling; Calcium signaling; Hepatocyte autophagy; NAFLD; SOCC/IP3R channel
    DOI:  https://doi.org/10.1007/s11010-021-04150-0
  5. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00007-5. [Epub ahead of print]150 113-145
    Autophagy and senescence, converging roles in pathophysiology as seen through mouse models.
    Andrew R J Young, Liam D Cassidy, Masashi Narita.
      Both senescence and autophagy have been strongly linked to aging and also cancer development. Numerous molecular, cellular, and physiological changes are known to correlate with an increasing age, yet our understanding of what underlies these changes or how they combine to give rise to the various pathologies associated with aging is still unclear. Levels of autophagy activity are known to decrease with advancing age, in a variety of organisms including mammals. Whereas senescent cells are known to accumulate in our bodies with age. Herein we review evidence from some elegant genetic mouse models linking senescence and also autophagy to aging and cancer. It is especially interesting to note the convergence in the pathological phenotypes of these two processes, senescence and autophagy, in these mouse models.
    Keywords:  Aging; Autophagy; Cancer; Cellular senescence; Mouse models
    DOI:  https://doi.org/10.1016/bs.acr.2021.02.001
  6. Nat Commun. 2021 04 14. 12(1): 2238
    Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.
    Benjamin Caballero, Mathieu Bourdenx, Enrique Luengo, Antonio Diaz, Peter Dongmin Sohn, Xu Chen, Chao Wang, Yves R Juste, Susanne Wegmann, Bindi Patel, Zapporah T Young, Szu Yu Kuo, Jose Antonio Rodriguez-Navarro, Hao Shao, Manuela G Lopez, Celeste M Karch, Alison M Goate, Jason E Gestwicki, Bradley T Hyman, Li Gan, Ana Maria Cuervo.
      Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.
    DOI:  https://doi.org/10.1038/s41467-021-22501-9
  7. Mol Cell Oncol. 2021 Mar 09. 8(2): 1890990
    p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control.
    Eeva-Liisa Eskelinen, Shun Kageyama, Masaaki Komatsu.
      Selective autophagy contributes to the degradation of condensates, such as sequestosome 1-bodies, also called p62/SQSTM1-bodies. We showed that endogenous p62 forms gel-like structures, which serve as platforms for autophagosome formation and nuclear factor erythroid 2-related factor 2 (NRF2) activation. Further, p62-mediated NRF2 activation is not cytotoxic, but combination of NRF2 activation with impaired bulk and selective autophagy causes liver injury.
    Keywords:  GABARAP; KEAP1; LC3; NRF2; autophagy; liquid-liquid phase separation; oxidative stress; p62/SQSTM1
    DOI:  https://doi.org/10.1080/23723556.2021.1890990
  8. Sci Rep. 2021 Apr 16. 11(1): 8392
    Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish.
    Masanori Inoue, Hiroaki Miyahara, Hiroshi Shiraishi, Nobuyuki Shimizu, Mika Tsumori, Kyoko Kiyota, Miwako Maeda, Ryohei Umeda, Tohru Ishitani, Reiko Hanada, Kenji Ihara, Toshikatsu Hanada.
      Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb-/-) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb-/- zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb-/- zebrafish. Indeed, excessive autophagy activation was observed in larsb-/- zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.
    DOI:  https://doi.org/10.1038/s41598-021-87879-4
  9. Front Oncol. 2021 ;11 555614
    Autophagic Heterogeneity in Gastric Adenocarcinoma.
    Ju-Yoon Yoon, Christine Brezden-Masley, Catherine J Streutker.
       Background and Aim: Gastric/gastroesophageal junction (GEJ) adenocarcinoma is a heterogeneous disease, with various etiologies and with tumors encompassing a spectrum of histologic and molecular subtypes. "Autophagy" includes two related but distinct homeostatic processes that promote cell survival under adverse conditions, namely macro- and chaperone-mediated autophagy. There is increasing evidence of the roles autophagy may play in tumorigenesis.
    Methods: Autophagic pathways were examined in the context of the heterogeneity intrinsic to gastric/GEJ adenocarcinoma, utilizing immunohistochemistry targeting specific proteins within the pathways (p62, LAMP2A, LC3B). We examined whole sections of normal and dysplastic gastric mucosa, as well as a tissue microarray of adenocarcinomas.
    Results: Dysplastic gastric epithelium was marked by frequent nuclear p62 and aberrant LAMP2A expression compared to normal. Examining the pattern of LC3B/cytoplasmic p62 immuno-reactivity in gastric adenocarcinoma demonstrated a predominant pattern of LC3BHigh/p62High staining (56/86, 65.1%), which has been previously associated with active, but impaired macroautophagy. There were no statistically significant associations seen between LC3B/cytoplasmic p62 staining patterns with tumor grade, histotype, or approximated TCGA molecular subtype. LAMP2A and nuclear p62 and staining patterns were also heterogeneous across the cohort, but with no statistically significant associations seen. The prognostic significance of the three proteins was limited, however high nuclear p62 levels were associated with worse overall survival (log-rank p-value = 0.0396).
    Conclusion: Our data demonstrate the dynamic nature of autophagic proteins in the gastric epithelium, and we expand the biological heterogeneity observed in gastric/GEJ adenocarcinoma to include autophagy.
    Keywords:  autophagy; autophagy (macroautophagy); biomarker; chaperone-mediated autophagy; gastric/GEJ adenocarcinoma
    DOI:  https://doi.org/10.3389/fonc.2021.555614
  10. Ageing Res Rev. 2021 Apr 07. pii: S1568-1637(21)00085-4. [Epub ahead of print]68 101338
    Autophagy in the diabetic heart: A potential pharmacotherapeutic target in diabetic cardiomyopathy.
    Saikat Dewanjee, Jayalakshmi Vallamkondu, Rajkumar Singh Kalra, Albin John, P Hemachandra Reddy, Ramesh Kandimalla.
      Association of diabetes with an elevated risk of cardiac failure has been clinically evident. Diabetes potentiates diastolic and systolic cardiac failure following the myocardial infarction that produces the cardiac muscle-specific microvascular complication, clinically termed as diabetic cardiomyopathy. Elevated susceptibility of diabetic cardiomyopathy is primarily caused by the generation of free radicals in the hyperglycemic milieu, compromising the myocardial contractility and normal cardiac functions with increasing redox insult, impaired mitochondria, damaged organelles, apoptosis, and cardiomyocytes fibrosis. Autophagy is essentially involved in the recycling/clearing the damaged organelles, cytoplasmic contents, and aggregates, which are frequently produced in cardiomyocytes. Although autophagy plays a vital role in maintaining the cellular homeostasis in diligent cardiac tissues, this process is frequently impaired in the diabetic heart. Given its clinical significance, accumulating evidence largely showed the functional aspects of autophagy in diabetic cardiomyopathy, elucidating its intricate protective and pathogenic outcomes. However, etiology and molecular readouts of these contrary autophagy activities in diabetic cardiomyopathy are not yet comprehensively assessed and translated. In this review, we attempted to assess the role of autophagy and its adaptations in the diabetic heart. To delineate the molecular consequences of these events, we provided detailed insights into the autophagy regulation pieces of machinery including the mTOR/AMPK, TFEB/ZNSCAN3, FOXOs, SIRTs, PINK1/Parkin, Nrf2, miRNAs, and others in the diabetic cardiomyopathy. Given the clinical significance of autophagy in the diabetic heart, we further discussed the potential pharmacotherapeutic strategies towards targeting autophagy. Taken together, the present report meticulously assessed autophagy, its adaptations, and molecular regulations in diabetic cardiomyopathy and reviewed the current autophagy-targeting strategies.
    Keywords:  Autophagy; Diabetes; Diabetic cardiomyopathy; Diabetic heart; Pharmacotherapy
    DOI:  https://doi.org/10.1016/j.arr.2021.101338
  11. Acta Neuropathol Commun. 2021 Apr 14. 9(1): 70
    Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington's disease.
    Ya Zhou, Thomas R Peskett, Christian Landles, John B Warner, Kirupa Sathasivam, Edward J Smith, Shu Chen, Ronald Wetzel, Hilal A Lashuel, Gillian P Bates, Helen R Saibil.
      Huntington's disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (1) multivesicular bodies (MVBs), or amphisomes and (2) autolysosomes or residual bodies. The organelles were often found in close-proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis.
    Keywords:  Amphisome; Autolysosome; Correlative light and electron microscopy; Electron tomography; Endolysosomal system; Exocytosis; Huntingtin aggregation; Huntington’s disease; Multivesicular body; Polyglutamine
    DOI:  https://doi.org/10.1186/s40478-021-01172-z
  12. Transl Androl Urol. 2021 Mar;10(3): 1006-1017
    A Web of Science-based scientometric analysis about mammalian target of rapamycin signaling pathway in kidney disease from 1986 to 2020.
    Lian-Zhong Wu, Yi-Qin Weng, Yi-Xin Ling, Shu-Juan Zhou, Xiao-Kai Ding, Si-Qi Wu, Kang Yu, Song-Fu Jiang, Yi Chen.
       Background: The mammalian target of rapamycin (mTOR) signaling pathway is vital for the regulation of cell metabolism, growth and proliferation in the kidney. This study aims to show current research focuses and predict future trends about mTOR pathway in kidney disease by the methods of scientometric analysis.
    Methods: We referred to publications from the Web of ScienceTM Core Collection (WoSCC) Database. Carrot2, VOSviewer and CiteSpace programs were applied to evaluate the distribution and contribution of authors, institutes and countries/regions of extensive bibliographic metadata, show current research focuses and predict future trends in kidney disease's area.
    Results: Until July 10, 2020, there are 2,585 manuscripts about mTOR signaling pathway in kidney disease in total and every manuscript is cited 27.39 times on average. The big name of course is the United States. Research hot spots include "diabetic nephropathy", "kidney transplantation", "autosomal dominant polycystic kidney disease", "tuberous sclerosis complex", "renal cell carcinoma" and "autophagy". Seven key clusters are detected, including "kidney transplantation", "autosomal dominant polycystic kidney disease", "renal transplantation", "renal cell carcinoma", "hamartin", "autophagy" and "tuberous sclerosis complex".
    Conclusions: Diabetic nephropathy, kidney transplantation, autosomal dominant polycystic kidney disease, tuberous sclerosis complex, renal cell carcinoma and autophagy are future research hot spots by utilizing scientometric analysis. In the future, it is necessary to research these fields.
    Keywords:  Bibliometrics; CiteSpace; TOR serine-threonine kinases; VOSviewer; kidney diseases
    DOI:  https://doi.org/10.21037/tau-20-1469
  13. Elife. 2021 04 13. pii: e62653. [Epub ahead of print]10
    A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage.
    Madhuja Samaddar, Jérôme Goudeau, Melissa Sanchez, David H Hall, K Adam Bohnert, Maria Ingaramo, Cynthia Kenyon.
      Somatic cells age and die, but the germ-cell lineage is immortal. In Caenorhabditis elegans, germline immortality involves proteostasis renewal at the beginning of each new generation, when oocyte maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen. Oocyte maturation signals are known to trigger protein-aggregate removal via lysosome acidification. Our findings suggest that lysosomes are acidified as a consequence of changes in endoplasmic reticulum activity that permit assembly of the lysosomal V-ATPase, which in turn allows lysosomes to clear the aggregates via microautophagy. We define two functions for mitochondria, both of which appear to be independent of ATP generation. Many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and somatic longevity.
    Keywords:  C. elegans; cell biology; genetic screen; germ lineage; lysosome acidification; oocyte maturation; proteostasis
    DOI:  https://doi.org/10.7554/eLife.62653
  14. Autophagy. 2021 Apr 12. 1-16
    WDR45, one gene associated with multiple neurodevelopmental disorders.
    Yingying Cong, Vincent So, Marina A J Tijssen, Dineke S Verbeek, Fulvio Reggiori, Mario Mauthe.
      The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat β-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders.Abbreviations: ATG/Atg: autophagy related; BPAN: ß-propeller protein associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; EEG: electroencephalograph; ENO2/neuron-specific enolase, enolase 2; EOEE: early-onset epileptic encephalopathy; ER: endoplasmic reticulum; ID: intellectual disability; IDR: intrinsically disordered region; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NCOA4: nuclear receptor coactivator 4; PtdIns3P: phosphatidylinositol-3-phosphate; RLS: Rett-like syndrome; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting.
    Keywords:  Autophagy; beta-propeller protein-associated neurodegeneration; brain iron accumulation; endoplasmic reticulum; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2021.1899669
  15. Front Cell Dev Biol. 2021 ;9 658995
    Lysosome (Dys)function in Atherosclerosis-A Big Weight on the Shoulders of a Small Organelle.
    André R A Marques, Cristiano Ramos, Gisela Machado-Oliveira, Otília V Vieira.
      Atherosclerosis is a progressive insidious chronic disease that underlies most of the cardiovascular pathologies, including myocardial infarction and ischemic stroke. The malfunctioning of the lysosomal compartment has a central role in the etiology and pathogenesis of atherosclerosis. Lysosomes are the degradative organelles of mammalian cells and process endogenous and exogenous substrates in a very efficient manner. Dysfunction of these organelles and consequent inefficient degradation of modified low-density lipoproteins (LDL) and apoptotic cells in atherosclerotic lesions have, therefore, numerous deleterious consequences for cellular homeostasis and disease progression. Lysosome dysfunction has been mostly studied in the context of the inherited lysosomal storage disorders (LSDs). However, over the last years it has become increasingly evident that the consequences of this phenomenon are more far-reaching, also influencing the progression of multiple acquired human pathologies, such as neurodegenerative diseases, cancer, and cardiovascular diseases (CVDs). During the formation of atherosclerotic plaques, the lysosomal compartment of the various cells constituting the arterial wall is under severe stress, due to the tremendous amounts of lipoproteins being processed by these cells. The uncontrolled uptake of modified lipoproteins by arterial phagocytic cells, namely macrophages and vascular smooth muscle cells (VSMCs), is the initial step that triggers the pathogenic cascade culminating in the formation of atheroma. These cells become pathogenic "foam cells," which are characterized by dysfunctional lipid-laden lysosomes. Here, we summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells. We further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality.
    Keywords:  atherosclerosis; autophagy; lysosomal storage diseases; lysosome dysfunction; oxidized lipids
    DOI:  https://doi.org/10.3389/fcell.2021.658995
  16. Exp Mol Med. 2021 Apr 14.
    The roles of the inhibitory autophagy regulator Rubicon in the heart: A new therapeutic target to prevent cardiac cell death.
    Jihoon Nah, Daniela Zablocki, Junichi Sadoshima.
      Autophagy contributes to the maintenance of cardiac homeostasis. The level of autophagy is dynamically altered in heart disease. Although autophagy is a promising therapeutic target, only a few selective autophagy activator candidates have been reported thus far. Rubicon is one of the few endogenous negative regulators of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon was initially identified as a component of the Class III PI3K complex, and it has multiple functions, not only in canonical autophagy but also in endosomal trafficking and inflammatory responses. This review summarizes the molecular action of Rubicon in canonical and noncanonical autophagy. We discuss the roles of Rubicon in cardiac stress and the therapeutic potential of Rubicon in cardiac diseases through its modulation of autophagy.
    DOI:  https://doi.org/10.1038/s12276-021-00600-3
  17. Matrix Biol. 2021 Apr 07. pii: S0945-053X(21)00040-8. [Epub ahead of print]
    A functional outside-in signaling network of proteoglycans and matrix molecules regulating autophagy.
    Thomas Neill, Aastha Kapoor, Christopher Xie, Simone Buraschi, Renato V Iozzo.
      Proteoglycans and selected extracellular matrix constituents are emerging as intrinsic and critical regulators of evolutionarily conversed, intracellular catabolic pathways. Often, these secreted molecules evoke sustained autophagy in a variety of cell types, tissues, and model systems. The unique properties of proteoglycans have ushered in a paradigmatic shift to broaden our understanding of matrix-mediated signaling cascades. The dynamic cellular pathway controlling autophagy is now linked to an equally dynamic and fluid signaling network embedded in a complex meshwork of matrix molecules. A rapidly emerging field of research encompasses multiple matrix-derived candidates, representing a menagerie of soluble matrix constituents including decorin, biglycan, endorepellin, endostatin, collagen VI and plasminogen kringle 5. These matrix constituents are pro-autophagic and simultaneously anti-angiogenic. In contrast, perlecan, laminin α2 chain, and lumican have anti-autophagic functions. Mechanistically, each matrix constituent linked to intracellular catabolic events engages a specific cell surface receptor that often converges on a common core of the autophagic machinery including AMPK, Peg3 and Beclin 1. We consider this matrix-evoked autophagy as non-canonical given that it occurs in an allosteric manner and is independent of nutrient availability or prevailing bioenergetics control. We propose that matrix-regulated autophagy is an important outside-in signaling mechanism for proper tissue homeostasis that could be therapeutically leveraged to combat a variety of diseases.
    Keywords:  angiogenesis; cancer; endothelial cells; proteoglycans; receptor tyrosine kinases
    DOI:  https://doi.org/10.1016/j.matbio.2021.04.001
  18. Proc Natl Acad Sci U S A. 2021 Apr 20. pii: e2101562118. [Epub ahead of print]118(16):
    A model for a partnership of lipid transfer proteins and scramblases in membrane expansion and organelle biogenesis.
    Alireza Ghanbarpour, Diana P Valverde, Thomas J Melia, Karin M Reinisch.
      The autophagy protein ATG2, proposed to transfer bulk lipid from the endoplasmic reticulum (ER) during autophagosome biogenesis, interacts with ER residents TMEM41B and VMP1 and with ATG9, in Golgi-derived vesicles that initiate autophagosome formation. In vitro assays reveal TMEM41B, VMP1, and ATG9 as scramblases. We propose a model wherein membrane expansion results from the partnership of a lipid transfer protein, moving lipids between the cytosolic leaflets of apposed organelles, and scramblases that reequilibrate the leaflets of donor and acceptor organelle membranes as lipids are depleted or augmented. TMEM41B and VMP1 are implicated broadly in lipid homeostasis and membrane dynamics processes in which their scrambling activities likely are key.
    Keywords:  ATG9A; TMEM41B; VMP1; scramblase
    DOI:  https://doi.org/10.1073/pnas.2101562118
  19. EMBO Mol Med. 2021 Apr 14. e13258
    Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.
    Reini E N van der Welle, Rebekah Jobling, Christian Burns, Paolo Sanza, Jan A van der Beek, Alfonso Fasano, Lan Chen, Fried J Zwartkruis, Susan Zwakenberg, Edward F Griffin, Corlinda Ten Brink, Tineke Veenendaal, Nalan Liv, Conny M A van Ravenswaaij-Arts, Henny H Lemmink, Rolph Pfundt, Susan Blaser, Carolina Sepulveda, Andres M Lozano, Grace Yoon, Teresa Santiago-Sim, Cedric S Asensio, Guy A Caldwell, Kim A Caldwell, David Chitayat, Judith Klumperman.
      Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41S285P and VPS41R662 * ; VPS41c.1423-2A>G and VPS41R662 * ) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41S285P enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41S285P /VPS41R662 * abolished the neuroprotective function of VPS41 against α-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.
    Keywords:  Autophagy; HOPS complex; TFEB/TFE3; lysosome-associated disorder; mTORC1
    DOI:  https://doi.org/10.15252/emmm.202013258
  20. Sci Rep. 2021 Apr 15. 11(1): 8313
    Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors.
    Philipp Rühl, Anna Scotto Rosato, Nicole Urban, Susanne Gerndt, Rachel Tang, Carla Abrahamian, Charlotte Leser, Jiansong Sheng, Archana Jha, Günter Vollmer, Michael Schaefer, Franz Bracher, Christian Grimm.
      The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the estrogen receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast cancer cell migration and invasion.
    DOI:  https://doi.org/10.1038/s41598-021-87817-4
  21. Cell Mol Life Sci. 2021 Apr 17.
    Role and mechanisms of autophagy in lung metabolism and repair.
    Xue Li, Fuxiaonan Zhao, An Wang, Peiyong Cheng, Huaiyong Chen.
      Mammalian lungs are metabolically active organs that frequently encounter environmental insults. Stress responses elicit protective autophagy in epithelial barrier cells and the supportive niche. Autophagy promotes the recycling of damaged intracellular organelles, denatured proteins, and other biological macromolecules for reuse as components required for lung cell survival. Autophagy, usually induced by metabolic defects, regulates cellular metabolism. Autophagy is a major adaptive response that protects cells and organisms from injury. Endogenous region-specific stem/progenitor cell populations are found in lung tissue, which are responsible for epithelial repair after lung damage. Additionally, glucose and fatty acid metabolism is altered in lung stem/progenitor cells in response to injury-related lung fibrosis. Autophagy deregulation has been observed to be involved in the development and progression of other respiratory diseases. This review explores the role and mechanisms of autophagy in regulating lung metabolism and epithelial repair.
    Keywords:  Asthma; COPD; Epithelial stem cells; Glycolysis; Idiopathic pulmonary fibrosis; Lung regeneration
    DOI:  https://doi.org/10.1007/s00018-021-03841-7
  22. Cancer Lett. 2021 Apr 13. pii: S0304-3835(21)00157-9. [Epub ahead of print]
    A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells.
    Yinghui Li, Yafang Li, Jingjing Yin, Chaoqun Wang, Ming Yang, Jiali Gu, Mei He, Hui Xu, Weichao Fu, Wenshan Zhang, Yongxin Ru, Xiaolei Liu, Ying Li, Yue Xin, Huier Gao, Xiangqun Xie, Yingdai Gao.
      There has been an increasing focus on the tumorigenic potential of leukemia initiating cells (LICs) in acute myeloid leukemia (AML). Despite the important role of selective autophagy in the life-long maintenance of hematopoietic stem cells (HSCs), cancer progression, and chemoresistance, the relationship between LICs and selective autophagy remains to be fully elucidated. Sequestosome 1 (SQSTM1), also known as p62, is a selective autophagy receptor for the degradation of ubiquitinated substrates, and its loss impairs leukemia progression in AML mouse models. In this study, we evaluated the underlying mechanisms of mitophagy in the survival of LICs with XRK3F2, a p62-ZZ inhibitor. We demonstrated that XRK3F2 selectively impaired LICs but spared normal HSCs in both mouse and patient-derived tumor xenograft (PDX) AML models. Mechanistically, we observed that XRK3F2 blocked mitophagy by inhibiting the binding of p62 with defective mitochondria. Our study not only evaluated the effectiveness and safety of XRK3F2 in LICs, but also demonstrated that mitophagy plays an indispensable role in the survival of LICs during AML development and progression, which can be impaired by blocking p62.
    Keywords:  AML; Autophagy; LICs; Small molecular compound
    DOI:  https://doi.org/10.1016/j.canlet.2021.04.003
  23. Genes Dev. 2021 Apr 01. 35(7-8): 449-469
    Interorganelle communication, aging, and neurodegeneration.
    Maja Petkovic, Caitlin E O'Brien, Yuh Nung Jan.
      Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics.
    Keywords:  aging; cellular homeostasis; communication; contact sites; endolysosomal pathway; interorganelle communication; lipid metabolism; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.1101/gad.346759.120
  24. Autophagy. 2021 Apr 05. 1-3
    Comment on "mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC".
    Ian G Ganley, Alexander J Whitworth, Thomas G McWilliams.
      
    DOI:  https://doi.org/10.1080/15548627.2021.1907269
  25. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00004-X. [Epub ahead of print]150 209-247
    The role of autophagy in escaping therapy-induced polyploidy/senescence.
    Magdalena Dudkowska, Karolina Staniak, Agnieszka Bojko, Ewa Sikora.
      Autophagy is an evolutionarily conserved process necessary to maintain cell homeostasis in response to various forms of stress such as nutrient deprivation and hypoxia as well as functioning to remove damaged molecules and organelles. The role of autophagy in cancer varies depending on the stage of cancer. Cancer therapeutics can also simultaneously evoke cancer cell senescence and ploidy increase. Both cancer cell senescence and polyploidization are reversible by depolyploidization giving rise to the progeny. Autophagy activation may be indispensable for cancer cell escape from senescence/polyploidy. As cancer cell polyploidy is proposed to be involved in cancer origin, the role of autophagy in polyploidization/depolyploidization of senescent cancer cells seems to be crucial. Accordingly, this review is an attempt to understand the complicated interrelationships between reversible cell senescence/polyploidy and autophagy.
    Keywords:  Autophagy; Cancer life cycle; Cancer origin; Polyploidization/depolyploidization; Therapy-induced senescence; mTOR
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.004
  26. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00005-1. [Epub ahead of print]150 147-208
    Autophagy and senescence: Insights from normal and cancer stem cells.
    Sarmistha Talukdar, Swadesh K Das, Luni Emdad, Paul B Fisher.
      Autophagy is a fundamental cellular process, which allows cells to adapt to metabolic stress through the degradation and recycling of intracellular components to generate macromolecular precursors and produce energy. Autophagy is also critical in maintaining cellular/tissue homeostasis, as well preserving immunity and preventing human disease. Deregulation of autophagic processes is associated with cancer, neurodegeneration, muscle and heart disease, infectious diseases and aging. Research on a variety of stem cell types establish that autophagy plays critical roles in normal and cancer stem cell quiescence, activation, differentiation, and self-renewal. Considering its critical function in regulating the metabolic state of stem cells, autophagy plays a dual role in the regulation of normal and cancer stem cell senescence, and cellular responses to various therapeutic strategies. The relationships between autophagy, senescence, dormancy and apoptosis frequently focus on responses to various forms of stress. These are interrelated processes that profoundly affect normal and abnormal human physiology that require further elucidation in cancer stem cells. This review provides a current perspective on autophagy and senescence in both normal and cancer stem cells.
    Keywords:  Autophagy; Cancer; Senescence; Stemness
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.005
  27. Mol Cell. 2021 Apr 05. pii: S1097-2765(21)00226-4. [Epub ahead of print]
    The dynamic mechanism of 4E-BP1 recognition and phosphorylation by mTORC1.
    Raphael Böhm, Stefan Imseng, Roman P Jakob, Michael N Hall, Timm Maier, Sebastian Hiller.
      The activation of cap-dependent translation in eukaryotes requires multisite, hierarchical phosphorylation of 4E-BP by the 1 MDa kinase mammalian target of rapamycin complex 1 (mTORC1). To resolve the mechanism of this hierarchical phosphorylation at the atomic level, we monitored by NMR spectroscopy the interaction of intrinsically disordered 4E binding protein isoform 1 (4E-BP1) with the mTORC1 subunit regulatory-associated protein of mTOR (Raptor). The N-terminal RAIP motif and the C-terminal TOR signaling (TOS) motif of 4E-BP1 bind separate sites in Raptor, resulting in avidity-based tethering of 4E-BP1. This tethering orients the flexible central region of 4E-BP1 toward the mTORC1 kinase site for phosphorylation. The structural constraints imposed by the two tethering interactions, combined with phosphorylation-induced conformational switching of 4E-BP1, explain the hierarchy of 4E-BP1 phosphorylation by mTORC1. Furthermore, we demonstrate that mTORC1 recognizes both free and eIF4E-bound 4E-BP1, allowing rapid phosphorylation of the entire 4E-BP1 pool and efficient activation of translation. Finally, our findings provide a mechanistic explanation for the differential rapamycin sensitivity of the 4E-BP1 phosphorylation sites.
    Keywords:  NMR spectroscopy; atypical kinase; hierarchical phosphorylation; intrinsically disordered protein; kinetic modelling; mTOR signaling; multi‑site binding; protein dynamics; target of rapamycin; translational control
    DOI:  https://doi.org/10.1016/j.molcel.2021.03.031
  28. Nat Commun. 2021 04 12. 12(1): 2183
    Autophagy of the m6A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis.
    Yan-Hong Cui, Seungwon Yang, Jiangbo Wei, Christopher R Shea, Wen Zhong, Fang Wang, Palak Shah, Muhammad G Kibriya, Xiaolong Cui, Habibul Ahsan, Chuan He, Yu-Ying He.
      Here we show that FTO as an N6-methyladenosine (m6A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m6A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m6A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m6A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m6A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.
    DOI:  https://doi.org/10.1038/s41467-021-22469-6
  29. Front Physiol. 2021 ;12 638983
    The Role of Autophagy in Skeletal Muscle Diseases.
    Qianghua Xia, Xubo Huang, Jieru Huang, Yongfeng Zheng, Michael E March, Jin Li, Yongjie Wei.
      Skeletal muscle is the most abundant type of tissue in human body, being involved in diverse activities and maintaining a finely tuned metabolic balance. Autophagy, characterized by the autophagosome-lysosome system with the involvement of evolutionarily conserved autophagy-related genes, is an important catabolic process and plays an essential role in energy generation and consumption, as well as substance turnover processes in skeletal muscles. Autophagy in skeletal muscles is finely tuned under the tight regulation of diverse signaling pathways, and the autophagy pathway has cross-talk with other pathways to form feedback loops under physiological conditions and metabolic stress. Altered autophagy activity characterized by either increased formation of autophagosomes or inhibition of lysosome-autophagosome fusion can lead to pathological cascades, and mutations in autophagy genes and deregulation of autophagy pathways have been identified as one of the major causes for a variety of skeleton muscle disorders. The advancement of multi-omics techniques enables further understanding of the molecular and biochemical mechanisms underlying the role of autophagy in skeletal muscle disorders, which may yield novel therapeutic targets for these disorders.
    Keywords:  AMPK; autophagy; mTOR; muscle cell homeostasis; skeletal muscle diseases; transcriptional regulation
    DOI:  https://doi.org/10.3389/fphys.2021.638983
  30. Cell Death Dis. 2021 Apr 14. 12(4): 397
    Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells.
    Yanli Bi, Longyuan Gong, Pengyuan Liu, Xiufang Xiong, Yongchao Zhao.
      ErbB2, a classical receptor tyrosine kinase, is frequently overexpressed in breast cancer cells. Although the role of ErbB2 in the transmission of extracellular signals to intracellular matrix has been widely studied, the functions of nuclear ErbB2 remain largely elusive. Here, we report a novel function of nuclear ErbB2 in repressing the transcription of DEPTOR, a direct inhibitor of mTOR. Nuclear ErbB2 directly binds to the consensus binding sequence in the DEPTOR promoter to repress its transcription. The kinase activity of ErbB2 is required for its nuclear translocation and transcriptional repression of DEPTOR. Moreover, the repressed DEPTOR by nuclear ErbB2 inhibits the induction of autophagy by activating mTORC1. Thus, our study reveals a novel mechanism for autophagy regulation by functional ErbB2, which translocates to the nucleus and acts as a transcriptional regulator to suppress DEPTOR transcription, leading to activation of the PI3K/AKT/mTOR pathway to inhibit autophagy.
    DOI:  https://doi.org/10.1038/s41419-021-03686-9
  31. Front Immunol. 2021 ;12 639682
    Making Insulin and Staying Out of Autoimmune Trouble: The Beta-Cell Conundrum.
    Alexia Carré, Roberto Mallone.
      Autoimmune type 1 diabetes (T1D) results from the intricate crosstalk of various immune cell types. CD8+ T cells dominate the pro-inflammatory milieu of islet infiltration (insulitis), and are considered as key effectors of beta-cell destruction, through the recognition of MHC Class I-peptide complexes. The pathways generating MHC Class I-restricted antigens in beta cells are poorly documented. Given their specialized insulin secretory function, the associated granule processing and degradation pathways, basal endoplasmic reticulum stress and susceptibility to additional stressors, alternative antigen processing and presentation (APP) pathways are likely to play a significant role in the generation of the beta-cell immunopeptidome. As direct evidence is missing, we here intersect the specificities of beta-cell function and the literature about APP in other cellular models to generate some hypotheses on APPs relevant to beta cells. We further elaborate on the potential role of these pathways in T1D pathogenesis, based on the current knowledge of antigens presented by beta cells. A better understanding of these pathways may pinpoint novel mechanisms amenable to therapeutic targeting to modulate the immunogenicity of beta cells.
    Keywords:  MHC class I; antigen presentation; antigen processing; autophagy; crinophagy; insulin granule; neo-epitopes; signal peptide
    DOI:  https://doi.org/10.3389/fimmu.2021.639682
  32. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00006-3. [Epub ahead of print]150 249-284
    Autophagy and PTEN in DNA damage-induced senescence.
    Arishya Sharma, Alexandru Almasan.
      The use of DNA-damaging agents such as radiotherapy and chemotherapy has been a mainstay treatment protocol for many cancers, including lung and prostate. Recently, FDA approval of inhibitors of DNA repair, and targeting innate immunity to enhance the efficacy of DNA-damaging agents have gained much attention. Yet, inherent or acquired resistance against DNA-damaging therapies persists as a fundamental drawback. While cancer eradication by causing cancer cell death through induction of apoptosis is the ultimate goal of anti-cancer treatments, autophagy and senescence are two major cellular responses induced by clinically tolerable doses of DNA-damaging therapies. Unlike apoptosis, autophagy and senescence can act as both pro-tumorigenic as well as tumor suppressive mechanisms. DNA damage-induced senescence is associated with a pro-inflammatory secretory phenotype, which contributes to reshaping the tumor- immune microenvironment. Moreover, PTEN (phosphatase and tensin homolog) is a tumor supressor deleted in many tumors, and has been implicated in both senescence and autophagy. This review presents an overview of the literature on the regulation and consequences of DNA damage- induced senescence in cancer cells, with a specific focus on autophagy and PTEN. Both autophagy and senescence occur concurrently in the same cells in response to DNA damaging agents. However, a deterministic relationship between these fundamental processes has been controversial. We present experimental evidence obtained with tumor cells, with a prime focus on two models of cancer, prostate and lung. A better understanding of mechanisms associated with DNA damage-induced cellular senescence is central to fully exploit the potential of DNA-damaging agents against cancer.
    Keywords:  Autophagy; DNA damage response; DNA repair; Lung cancer; PTEN; Prostate cancer; Radiotherapy; Senescence; TMPRSS2-ERG fusion gene; USP14
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.006
  33. Signal Transduct Target Ther. 2021 Apr 16. 6(1): 152
    Nlp promotes autophagy through facilitating the interaction of Rab7 and FYCO1.
    Wenchang Xiao, Danna Yeerken, Jia Li, Zhangfu Li, Lanfang Jiang, Dan Li, Ming Fu, Liying Ma, Yongmei Song, Weimin Zhang, Qimin Zhan.
      Autophagy is the main degradation pathway to eliminate long-lived and aggregated proteins, aged or malfunctioning organelles, which is essential for the intracellular homeostasis and prevention of malignant transformation. Although the processes of autophagosome biogenesis have been well illuminated, the mechanism of autophagosome transport remains largely unclear. In this study, we demonstrated that the ninein-like protein (Nlp), a well-characterized centrosomal associated protein, was able to modulate autophagosome transport and facilitate autophagy. During autophagy, Nlp colocalized with autophagosomes and physically interacted with autophagosome marker LC3, autophagosome sorting protein Rab7 and its downstream effector FYCO1. Interestingly, Nlp enhanced the interaction between Rab7 and FYCO1, thus accelerated autophagic flux and the formation of autophagolysosomes. Furthermore, compared to the wild-type mice, NLP deficient mice treated with chemical agent DMBA were prone to increased incidence of hepatomegaly and liver cancer, which were tight associated with the hepatic autophagic defect. Taken together, our findings provide a new insight for the first time that the well-known centrosomal protein Nlp is also a new regulator of autophagy, which promotes the interaction of Rab7 and FYCO1 and facilitates the formation of autophagolysosome.
    DOI:  https://doi.org/10.1038/s41392-021-00543-1
  34. J Exp Med. 2021 Jun 07. pii: e20201776. [Epub ahead of print]218(6):
    Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity.
    Guillaume Harlé, Camille Kowalski, Juan Dubrot, Dale Brighouse, Gaëlle Clavel, Robert Pick, Natacha Bessis, Jennifer Niven, Christoph Scheiermann, Monique Gannagé, Stéphanie Hugues.
      Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.
    DOI:  https://doi.org/10.1084/jem.20201776
  35. Sci Adv. 2021 Apr;pii: eabe5544. [Epub ahead of print]7(16):
    Kog1/Raptor mediates metabolic rewiring during nutrient limitation by controlling SNF1/AMPK activity.
    Zeenat Rashida, Rajalakshmi Srinivasan, Meghana Cyanam, Sunil Laxman.
      In changing environments, cells modulate resource budgeting through distinct metabolic routes to control growth. Accordingly, the TORC1 and SNF1/AMPK pathways operate contrastingly in nutrient replete or limited environments to maintain homeostasis. The functions of TORC1 under glucose and amino acid limitation are relatively unknown. We identified a modified form of the yeast TORC1 component Kog1/Raptor, which exhibits delayed growth exclusively during glucose and amino acid limitations. Using this, we found a necessary function for Kog1 in these conditions where TORC1 kinase activity is undetectable. Metabolic flux and transcriptome analysis revealed that Kog1 controls SNF1-dependent carbon flux apportioning between glutamate/amino acid biosynthesis and gluconeogenesis. Kog1 regulates SNF1/AMPK activity and outputs and mediates a rapamycin-independent activation of the SNF1 targets Mig1 and Cat8. This enables effective glucose derepression, gluconeogenesis activation, and carbon allocation through different pathways. Therefore, Kog1 centrally regulates metabolic homeostasis and carbon utilization during nutrient limitation by managing SNF1 activity.
    DOI:  https://doi.org/10.1126/sciadv.abe5544
  36. Sci Signal. 2021 Apr 13. pii: eabe4509. [Epub ahead of print]14(678):
    mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif.
    Timothy R Baffi, Gema Lordén, Jacob M Wozniak, Andreas Feichtner, Wayland Yeung, Alexandr P Kornev, Charles C King, Jason C Del Rio, Ameya J Limaye, Julius Bogomolovas, Christine M Gould, Ju Chen, Eileen J Kennedy, Natarajan Kannan, David J Gonzalez, Eduard Stefan, Susan S Taylor, Alexandra C Newton.
      The complex mTORC2 is accepted to be the kinase that controls the phosphorylation of the hydrophobic motif, a key regulatory switch for AGC kinases, although whether mTOR directly phosphorylates this motif remains controversial. Here, we identified an mTOR-mediated phosphorylation site that we termed the TOR interaction motif (TIM; F-x3-F-pT), which controls the phosphorylation of the hydrophobic motif of PKC and Akt and the activity of these kinases. The TIM is invariant in mTORC2-dependent AGC kinases, is evolutionarily conserved, and coevolved with mTORC2 components. Mutation of this motif in Akt1 and PKCβII abolished cellular kinase activity by impairing activation loop and hydrophobic motif phosphorylation. mTORC2 directly phosphorylated the PKC TIM in vitro, and this phosphorylation event was detected in mouse brain. Overexpression of PDK1 in mTORC2-deficient cells rescued hydrophobic motif phosphorylation of PKC and Akt by a mechanism dependent on their intrinsic catalytic activity, revealing that mTORC2 facilitates the PDK1 phosphorylation step, which, in turn, enables autophosphorylation. Structural analysis revealed that PKC homodimerization is driven by a TIM-containing helix, and biophysical proximity assays showed that newly synthesized, unphosphorylated PKC dimerizes in cells. Furthermore, disruption of the dimer interface by stapled peptides promoted hydrophobic motif phosphorylation. Our data support a model in which mTORC2 relieves nascent PKC dimerization through TIM phosphorylation, recruiting PDK1 to phosphorylate the activation loop and triggering intramolecular hydrophobic motif autophosphorylation. Identification of TIM phosphorylation and its role in the regulation of PKC provides the basis for AGC kinase regulation by mTORC2.
    DOI:  https://doi.org/10.1126/scisignal.abe4509
  37. STAR Protoc. 2021 Jun 18. 2(2): 100408
    3D quantification of autophagy activation and autophagosome-to-mitochondria recruitment in a Drosophila model of Parkinson's disease.
    Susana J Gutierrez-Luke, Amber N Juba, Giulia Bertolin, Lori M Buhlman.
      Here, we describe a protocol for comprehensive quantification of autophagosome recruitment to mitochondria as an early step in mitophagy. Data collected using this protocol can be useful in the study of neurodegenerative disease, cancer, and metabolism-related disorders using models in which co-expression of mito-GFP and mCherry-Atg8a is feasible. This protocol has the advantage of assessment in an in vivo model organism (Drosophila melanogaster), where tissue-specific mitophagy can be investigated. For complete details on the use and execution of this protocol, please refer to (Cackovic et al., 2018).
    Keywords:  Cell Biology; Microscopy; Model Organisms; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2021.100408
  38. Mol Med Rep. 2021 Jun;pii: 443. [Epub ahead of print]23(6):
    Zinc‑finger E‑box‑binding homeobox 1 alleviates acute kidney injury by activating autophagy and the AMPK/mTOR pathway.
    Dehua Sun, Xiaohua Liu, Lijuan Zhu, Bin Zhang.
      Zinc‑finger E‑box‑binding homeobox 1 (ZEB1) is involved in epithelial‑mesenchymal transition. In the present study, the protective effect of ZEB1 on acute kidney injury (AKI) was explored. The cecal ligation and puncture (CLP) method was performed to establish the AKI model in rats. ZEB1 expression, blood urea nitrogen (BUN) and serum creatinine (SCr) levels, inflammation [interleukin (IL)‑1β, IL‑6, and tumour necrosis factor‑α], phosphorylated AMP‑activated protein kinase (p‑AMPK) and phosphorylated mammalian target of rapamycin (p‑mTOR) expression, and histopathological changes in CLP‑induced AKI rats were assessed. AMPK inhibitor dorsomorphin (DM) was intraperitoneally injected to determine the effect of ZEB1 on AKI and the regulatory mechanism involving the AMPK/mTOR pathway. CLP downregulated ZEB1 expression, increased BUN and SCr levels, promoted inflammation and apoptosis, and increased the acute kidney score in the kidney tissues of CLP‑induced AKI rats. Autophagy and the AMPK/mTOR pathway were blocked in CLP‑induced AKI rats. ZEB1 overexpression inhibited inflammation and apoptosis, reduced BUN and SCr levels, and activated autophagy and the AMPK/mTOR pathway in CLP‑induced AKI rats. The protective effect of ZEB1 overexpression on AKI was reversed by DM. Thus, ZEB1 was revealed to alleviate CLP‑induced AKI by activating autophagy and the AMPK/mTOR pathway.
    DOI:  https://doi.org/10.3892/mmr.2021.12082
  39. Bioessays. 2021 Apr 14. e2100014
    NIPSNAP protein family emerges as a sensor of mitochondrial health.
    Esmat Fathi, Jay M Yarbro, Ramin Homayouni.
      Since their discovery over two decades ago, the molecular and cellular functions of the NIPSNAP family of proteins (NIPSNAPs) have remained elusive until recently. NIPSNAPs interact with a variety of mitochondrial and cytoplasmic proteins. They have been implicated in multiple cellular processes and associated with different physiologic and pathologic conditions, including pain transmission, Parkinson's disease, and cancer. Recent evidence demonstrated a direct role for NIPSNAP1 and NIPSNAP2 proteins in regulation of mitophagy, a process that is critical for cellular health and maintenance. Importantly, NIPSNAPs contain a 110 amino acid domain that is evolutionary conserved from mammals to bacteria. However, the molecular function of the conserved NIPSNAP domain and its potential role in mitophagy have not been explored. It stands to reason that the highly conserved NIPSNAP domain interacts with a substrate that is ubiquitously present across all species and can perhaps act as a sensor for mitochondrial health.
    Keywords:  Alzheimer's disease; Parkinson's disease; Sirtuin3; metabolism; mitophagy
    DOI:  https://doi.org/10.1002/bies.202100014
  40. Food Nutr Res. 2021 ;65
    Fisetin inhibits inflammation and induces autophagy by mediating PI3K/AKT/mTOR signaling in LPS-induced RAW264.7 cells.
    Yue Sun, Hong Qin, Huihui Zhang, Xiangling Feng, Lina Yang, De-Xing Hou, Jihua Chen.
       Background: Fisetin, a natural potent flavonoid, has various beneficial, pharmacological activities. In this study, we investigated expression changes of the fisetin regulating genes in lipopolysaccharide (LPS)-treated RAW264.7 cells and explored the role of fisetin in inflammation and autophagy.
    Methods and results: Microarray analysis identified 1,071 genes that were regulated by fisetin in LPS-treated RAW264.7 cells, and these genes were mainly related to the process of immune system response. Quantitative real-time polymerase chain reaction and Bio-Plex analysis indicated that fisetin decreased the expression and secretion of several inflammatory cytokines in cells administered with LPS. Western blot analysis and immunofluorescence assay showed that fisetin decreased microtubule-associated protein 1 light-chain 3B (LC3B) and lysosome-associated membrane protein 1 (LAMP1) expression in LPS-treated cells, while the autophagy inhibitor chloroquine (CQ) could partially reverse this effect. In addition, fisetin reduced the elevated expression of p-PI3K, p-AKT and p-mTOR induced by LPS in a concentration-dependent manner.
    Conclusions: Fisetin diminished the expression and secretion of inflammatory cytokines and facilitated autophagosome-lysosome fusion and degradation in LPS-treated RAW264.7 cells via inhibition of the PI3K/AKT/mTOR signaling pathway. Overall, the results of this study provide new clues for the anti-inflammatory mechanism of fisetin and explain the crosstalk between autophagy and inflammation to some extent.
    Keywords:  PI3K/AKT/mTOR pathway; autophagy; fisetin; inflammatory response; macrophage
    DOI:  https://doi.org/10.29219/fnr.v65.6355
  41. J Cell Physiol. 2021 Apr 12.
    Roles of FAM134B in diseases from the perspectives of organelle membrane morphogenesis and cellular homeostasis.
    Luoyi Zhu, Xinxia Wang, Yizhen Wang.
      Family with sequence similarity 134 member B (FAM134B)/RETREG1/JK1 is a novel gene with recently reported roles in various diseases. Understanding the function and mechanism of action of FAM134B is necessary to develop disease therapies. Notably, emerging data are clarifying the molecular mechanisms of FAM134B function in organelle membrane morphogenesis and the regulation of signaling pathways, such as the Wnt and AKT signaling pathways. In addition, transcription factors, RNA N6 -methyladenosine-mediated epigenetic regulation, microRNA, and small molecules are involved in the regulation of FAM134B expression. This review comprehensively considers recent studies on the role of FAM134B and its potential mechanisms in neurodegenerative diseases, obesity, viral diseases, cancer, and other diseases. The functions of FAM134B in maintaining cell homeostasis by regulating Golgi morphology, endoplasmic reticulum autophagy, and mitophagy are also highlighted, which may be the underlying mechanism of FAM134B gene mutation-induced diseases. Moreover, the molecular mechanisms of the FAM134B function during numerous biological processes are discussed. This review provides novel insights into the functions and mechanisms of FAM134B in various diseases, which will inform the development of effective drugs to treat diseases.
    Keywords:  ER-phagy; FAM134B; Golgi apparatus; HSAN ⅡB; cancer; mitophagy; obesity; signal pathways
    DOI:  https://doi.org/10.1002/jcp.30377
  42. Nature. 2021 Apr 14.
    Organelle degradation in the lens by PLAAT phospholipases.
    Hideaki Morishita, Tomoya Eguchi, Satoshi Tsukamoto, Yuriko Sakamaki, Satoru Takahashi, Chieko Saito, Ikuko Koyama-Honda, Noboru Mizushima.
      The eye lens of vertebrates is composed of fibre cells in which all membrane-bound organelles undergo degradation during terminal differentiation to form an organelle-free zone1. The mechanism that underlies this large-scale organelle degradation remains largely unknown, although it has previously been shown to be independent of macroautophagy2,3. Here we report that phospholipases in the PLAAT (phospholipase A/acyltransferase, also known as HRASLS) family-Plaat1 (also known as Hrasls) in zebrafish and PLAAT3 (also known as HRASLS3, PLA2G16, H-rev107 or AdPLA) in mice4-6-are essential for the degradation of lens organelles such as mitochondria, the endoplasmic reticulum and lysosomes. Plaat1 and PLAAT3 translocate from the cytosol to various organelles immediately before organelle degradation, in a process that requires their C-terminal transmembrane domain. The translocation of Plaat1 to organelles depends on the differentiation of fibre cells and damage to organelle membranes, both of which are mediated by Hsf4. After the translocation of Plaat1 or PLAAT3 to membranes, the phospholipase induces extensive organelle rupture that is followed by complete degradation. Organelle degradation by PLAAT-family phospholipases is essential for achieving an optimal transparency and refractive function of the lens. These findings expand our understanding of intracellular organelle degradation and provide insights into the mechanism by which vertebrates acquired transparent lenses.
    DOI:  https://doi.org/10.1038/s41586-021-03439-w
  43. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00002-6. [Epub ahead of print]150 1-74
    Autophagy and senescence in cancer therapy.
    Nipa H Patel, Sarah Bloukh, Enas Alwohosh, Ahmad Alhesa, Tareq Saleh, David A Gewirtz.
      Tumor cells can undergo diverse responses to cancer therapy. While apoptosis represents the most desirable outcome, tumor cells can alternatively undergo autophagy and senescence. Both autophagy and senescence have the potential to make complex contributions to tumor cell survival via both cell autonomous and cell non-autonomous pathways. The induction of autophagy and senescence in tumor cells, preclinically and clinically, either individually or concomitantly, has generated interest in the utilization of autophagy modulating and senolytic therapies to target autophagy and senescence, respectively. This chapter summarizes the current evidence for the promotion of autophagy and senescence as fundamental responses to cancer therapy and discusses the complexity of their functional contributions to cell survival and disease outcomes. We also highlight current modalities designed to exploit autophagy and senescence in efforts to improve the efficacy of cancer therapy.
    Keywords:  Apoptosis; Autophagy; Cancer; Chemotherapy; Cytoprotective; Dormancy; Durable growth arrest; Radiation; SASP; Senescence; Senolytics
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.002
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