bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2021‒01‒31
thirty-two papers selected by
Viktor Korolchuk, Newcastle University
  1. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
  2. Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders.
  3. Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy.
  4. ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?
  5. TOR Signaling Pathway in Cardiac Aging and Heart Failure.
  6. Cargo Recognition and Function of Selective Autophagy Receptors in Plants.
  7. ER-Phagy, ER Homeostasis, and ER Quality Control: Implications for Disease.
  8. IRGM1 links mitochondrial quality control to autoimmunity.
  9. Hijacking Endocytosis and Autophagy in Extracellular Vesicle Communication: Where the Inside Meets the Outside.
  10. VCP/p97 regulates Beclin-1-dependent autophagy initiation.
  11. Getting picky with the lysosome membrane.
  12. Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex.
  13. TFEB Supports Pancreatic Cancer Growth through the Transcriptional Regulation of Glutaminase.
  14. The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit selective autophagy.
  15. Basic fibroblast growth factor accelerates myelin debris clearance through activating autophagy to facilitate early peripheral nerve regeneration.
  16. Urban Aerosol Particulate Matter Promotes Necrosis and Autophagy via Reactive Oxygen Species-Mediated Cellular Disorders that are Accompanied by Cell Cycle Arrest in Retinal Pigment Epithelial Cells.
  17. Membrane binding and homodimerization of Atg16 via two distinct protein regions is essential for autophagy in yeast.
  18. Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling.
  19. Optineurin deletion disrupts metabotropic glutamate receptor 5-mediated regulation of ERK1/2, GSK3β/ZBTB16, mTOR/ULK1 signaling in autophagy.
  20. Mitophagy of polarized sperm-derived mitochondria after fertilization.
  21. Lack of Autophagy Induction by Lithium Decreases Neuroprotective Effects in the Striatum of Aged Rats.
  22. Catalase deficiency induces reactive oxygen species mediated pexophagy and cell death in the liver during prolonged fasting.
  23. Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin.
  24. Defective Autophagy and Mitophagy in Aging and Alzheimer's Disease.
  25. Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition.
  26. Autophagy proteins and its homeostasis in cellular environment.
  27. Aging and age-related diseases: from mechanisms to therapeutic strategies.
  28. MiT/TFE Family of Transcription Factors: An Evolutionary Perspective.
  29. Autophagy status as a gateway for stress-induced catecholamine interplay in neurodegeneration.
  30. Autophagy and Exosomes Relationship in Cancer: Friends or Foes?
  31. The complex network of mTOR signaling in the heart.
  32. Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing.
  1. Cell. 2021 Jan 18. pii: S0092-8674(20)31694-9. [Epub ahead of print]
    G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
    Genomics England Research Consortium
      Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.
    Keywords:  G3BP1; G3BP2; TSC complex; cancer; lysosome; mTORC1; metabolism; neuronal function; stress granule
    DOI:  https://doi.org/10.1016/j.cell.2020.12.024
  2. Acta Neuropathol. 2021 Jan 30.
    Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders.
    Daniel Erskine, David Koss, Viktor I Korolchuk, Tiago F Outeiro, Johannes Attems, Ian McKeith.
      Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.
    Keywords:  Alpha-synuclein; Autophagy; Catabolism; Lewy body; Lipid metabolism; Mitochondria
    DOI:  https://doi.org/10.1007/s00401-021-02266-7
  3. Autophagy. 2021 Jan 26. 1-26
    Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy.
    Waka Kojima, Koji Yamano, Hidetaka Kosako, Kenichiro Imai, Reika Kikuchi, Keiji Tanaka, Noriyuki Matsuda.
      Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.
    Keywords:  Mitophagy; parkin; phagophore; pink1; starvation; wd40
    DOI:  https://doi.org/10.1080/15548627.2021.1874133
  4. Front Cell Dev Biol. 2020 ;8 599048
    ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?
    Venturina Stagni, Alessandra Ferri, Claudia Cirotti, Daniela Barilà.
      Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.
    Keywords:  ATM kinase; DDR; ataxia-telangiectasia; autophagy; senescence
    DOI:  https://doi.org/10.3389/fcell.2020.599048
  5. Biomolecules. 2021 Jan 27. pii: 168. [Epub ahead of print]11(2):
    TOR Signaling Pathway in Cardiac Aging and Heart Failure.
    Nastaran Daneshgar, Peter S Rabinovitch, Dao-Fu Dai.
      Mechanistic Target of Rapamycin (mTOR) signaling is a key regulator of cellular metabolism, integrating nutrient sensing with cell growth. Over the past two decades, studies on the mTOR pathway have revealed that mTOR complex 1 controls life span, health span, and aging by modulating key cellular processes such as protein synthesis, autophagy, and mitochondrial function, mainly through its downstream substrates. Thus, the mTOR pathway regulates both physiological and pathological processes in the heart from embryonic cardiovascular development to maintenance of cardiac homeostasis in postnatal life. In this regard, the dysregulation of mTOR signaling has been linked to many age-related pathologies, including heart failure and age-related cardiac dysfunction. In this review, we highlight recent advances of the impact of mTOR complex 1 pathway and its regulators on aging and, more specifically, cardiac aging and heart failure.
    Keywords:  aging; caloric restriction; cardiac aging; heart failure; mTOR; rapamycin
    DOI:  https://doi.org/10.3390/biom11020168
  6. Int J Mol Sci. 2021 Jan 20. pii: E1013. [Epub ahead of print]22(3):
    Cargo Recognition and Function of Selective Autophagy Receptors in Plants.
    Shuwei Luo, Xifeng Li, Yan Zhang, Yunting Fu, Baofang Fan, Cheng Zhu, Zhixiang Chen.
      Autophagy is a major quality control system for degradation of unwanted or damaged cytoplasmic components to promote cellular homeostasis. Although non-selective bulk degradation of cytoplasm by autophagy plays a role during cellular response to nutrient deprivation, the broad roles of autophagy are primarily mediated by selective clearance of specifically targeted components. Selective autophagy relies on cargo receptors that recognize targeted components and recruit them to autophagosomes through interaction with lapidated autophagy-related protein 8 (ATG8) family proteins anchored in the membrane of the forming autophagosomes. In mammals and yeast, a large collection of selective autophagy receptors have been identified that mediate the selective autophagic degradation of organelles, aggregation-prone misfolded proteins and other unwanted or nonnative proteins. A substantial number of selective autophagy receptors have also been identified and functionally characterized in plants. Some of the autophagy receptors in plants are evolutionarily conserved with homologs in other types of organisms, while a majority of them are plant-specific or plant species-specific. Plant selective autophagy receptors mediate autophagic degradation of not only misfolded, nonactive and otherwise unwanted cellular components but also regulatory and signaling factors and play critical roles in plant responses to a broad spectrum of biotic and abiotic stresses. In this review, we summarize the research on selective autophagy in plants, with an emphasis on the cargo recognition and the biological functions of plant selective autophagy receptors.
    Keywords:  ER-phagy; NBR1; aggrephagy; autophagy; drought tolerance; plants stress responses; plastid recycling; selective autophagy receptors
    DOI:  https://doi.org/10.3390/ijms22031013
  7. Trends Biochem Sci. 2021 Jan 25. pii: S0968-0004(20)30325-X. [Epub ahead of print]
    ER-Phagy, ER Homeostasis, and ER Quality Control: Implications for Disease.
    Susan Ferro-Novick, Fulvio Reggiori, Jeffrey L Brodsky.
      Lysosomal degradation of endoplasmic reticulum (ER) fragments by autophagy, termed ER-phagy or reticulophagy, occurs under normal as well as stress conditions. The recent discovery of multiple ER-phagy receptors has stimulated studies on the roles of ER-phagy. We discuss how the ER-phagy receptors and the cellular components that work with these receptors mediate two important functions: ER homeostasis and ER quality control. We highlight that ER-phagy plays an important role in alleviating ER expansion induced by ER stress, and acts as an alternative disposal pathway for misfolded proteins. We suggest that the latter function explains the emerging connection between ER-phagy and disease. Additional ER-phagy-associated functions and important unanswered questions are also discussed.
    Keywords:  autophagy receptor; endoplasmic reticulum; human disease; macro-ER-phagy; micro-ER-phagy; proteostasis; reticulophagy
    DOI:  https://doi.org/10.1016/j.tibs.2020.12.013
  8. Nat Immunol. 2021 Jan 28.
    IRGM1 links mitochondrial quality control to autoimmunity.
    Prashant Rai, Kyathanahalli S Janardhan, Julie Meacham, Jennifer H Madenspacher, Wan-Chi Lin, Peer W F Karmaus, Jennifer Martinez, Quan-Zhen Li, Mei Yan, Jialiu Zeng, Mark W Grinstaff, Orian S Shirihai, Gregory A Taylor, Michael B Fessler.
      Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5, ATG7 and IRGM have been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA-dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1-/- tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease.
    DOI:  https://doi.org/10.1038/s41590-020-00859-0
  9. Front Cell Dev Biol. 2020 ;8 595515
    Hijacking Endocytosis and Autophagy in Extracellular Vesicle Communication: Where the Inside Meets the Outside.
    Giona Pedrioli, Paolo Paganetti.
      Extracellular vesicles, phospholipid bilayer-membrane vesicles of cellular origin, are emerging as nanocarriers of biological information between cells. Extracellular vesicles transport virtually all biologically active macromolecules (e.g., nucleotides, lipids, and proteins), thus eliciting phenotypic changes in recipient cells. However, we only partially understand the cellular mechanisms driving the encounter of a soluble ligand transported in the lumen of extracellular vesicles with its cytosolic receptor: a step required to evoke a biologically relevant response. In this context, we review herein current evidence supporting the role of two well-described cellular transport pathways: the endocytic pathway as the main entry route for extracellular vesicles and the autophagic pathway driving lysosomal degradation of cytosolic proteins. The interplay between these pathways may result in the target engagement between an extracellular vesicle cargo protein and its cytosolic target within the acidic compartments of the cell. This mechanism of cell-to-cell communication may well own possible implications in the pathogenesis of neurodegenerative disorders.
    Keywords:  aggregation; autophagy; cargo; cell-to-cell communication; endocytosis; extracellular vesicles; lysosome; neurodegeneration
    DOI:  https://doi.org/10.3389/fcell.2020.595515
  10. Nat Chem Biol. 2021 Jan 28.
    VCP/p97 regulates Beclin-1-dependent autophagy initiation.
    Sandra M Hill, Lidia Wrobel, Avraham Ashkenazi, Marian Fernandez-Estevez, Keith Tan, Roland W Bürli, David C Rubinsztein.
      Autophagy is an essential cellular process that removes harmful protein species, and autophagy upregulation may be able to protect against neurodegeneration and various pathogens. Here, we have identified the essential protein VCP/p97 (VCP, valosin-containing protein) as a novel regulator of autophagosome biogenesis, where VCP regulates autophagy induction in two ways, both dependent on Beclin-1. Utilizing small-molecule inhibitors of VCP ATPase activity, we show that VCP stabilizes Beclin-1 levels by promoting the deubiquitinase activity of ataxin-3 towards Beclin-1. VCP also regulates the assembly and activity of the Beclin-1-containing phosphatidylinositol-3-kinase (PI3K) complex I, thus regulating the production of PI(3)P, a key signaling lipid responsible for the recruitment of downstream autophagy factors. A decreased level of VCP, or inhibition of its ATPase activity, impairs starvation-induced production of PI(3)P and limits downstream recruitment of WIPI2, ATG16L and LC3, thereby decreasing autophagosome formation, illustrating an important role for VCP in early autophagy initiation.
    DOI:  https://doi.org/10.1038/s41589-020-00726-x
  11. Autophagy. 2021 Jan 26. 1-3
    Getting picky with the lysosome membrane.
    Chan Lee, Michael Overholtzer.
      Lysosomes play an essential role in quality control mechanisms by functioning as the primary digestive system in mammalian cells. However, the quality control mechanisms governing healthy lysosomes are not fully understood. Using a method to study lysosome membrane turnover, we discovered that LC3-lipidation on the lysosome limiting membrane is involved in invagination and formation of intralumenal vesicles, an activity known as microautophagy. This activity occurs in response to metabolic stress, in the form of glucose starvation, or osmotic stress induced by treatment with lysosomotropic compounds. Cells rendered deficient in the ability to lipidate LC3 through knockout of ATG5 show reduced ability to regulate lysosome size and degradative function in response to stress. These findings demonstrate that cells can adapt to changing metabolic conditions by turning over selective portions of the lysosomal membrane, using a mechanism that involves lysosome-targeted LC3 lipidation and the induction of selective microautophagy.
    Keywords:  ATG5; LC3; autophagy; lysophagy; microautophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1877935
  12. Acta Pharmacol Sin. 2021 Jan 25.
    Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex.
    Xiao-Jing Li, Yuan-Yuan Zhang, Yu-Hua Fu, Hao Zhang, He-Xuan Li, Quan-Fu Li, Hai-Ling Li, Ren-Ke Tan, Chen-Xiao Jiang, Wei Jiang, Zeng-Xia Li, Cheng Luo, Bo-Xun Lu, Yong-Jun Dang.
      Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by toxic aggregates of mutant huntingtin protein (mHTT) in the brain. Decreasing mHTT is a potential strategy for therapeutic purpose of HD. Valosin-containing protein (VCP/p97) is a crucial regulator of proteostasis, which regulates the degradation of damaged protein through proteasome and autophagy pathway. Since VCP has been implicated in pathogenesis of HD as well as other neurodegenerative diseases, small molecules that specifically regulate the activity of VCP may be of therapeutic benefits for HD patients. In this study we established a high-throughput screening biochemical assay for VCP ATPase activity measurement and identified gossypol, a clinical approved drug in China, as a novel modulator of VCP. Gossypol acetate dose-dependently inhibited the enzymatic activity of VCP in vitro with IC50 of 6.53±0.6 μM. We further demonstrated that gossypol directly bound to the interface between the N and D1 domains of VCP. Gossypol acetate treatment not only lowered mHTT levels and rescued HD-relevant phenotypes in HD patient iPS-derived Q47 striatal neurons and HD knock-in mouse striatal cells, but also improved motor function deficits in both Drosophila and mouse HD models. Taken together, gossypol acetate acted through a gain-of-function way to induce the formation of VCP-LC3-mHTT ternary complex, triggering autophagic degradation of mHTT. This study reveals a new strategy for treatment of HD and raises the possibility that an existing drug can be repurposed as a new treatment of neurodegenerative diseases.
    Keywords:  Huntington disease; LC3; VCP; autophagic degradation; drug reposition; gossypol acetate; mutant huntingtin protein
    DOI:  https://doi.org/10.1038/s41401-020-00605-0
  13. Cancers (Basel). 2021 Jan 27. pii: 483. [Epub ahead of print]13(3):
    TFEB Supports Pancreatic Cancer Growth through the Transcriptional Regulation of Glutaminase.
    Ji Hye Kim, Jinyoung Lee, Young-Ra Cho, So-Yeon Lee, Gi-Jun Sung, Dong-Myung Shin, Kyung-Chul Choi, Jaekyoung Son.
      Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, we show that pancreatic cancer cells exhibit a significantly elevated TFEB expression compared with normal tissue samples and that the genetic inhibition of TFEB results in a significant inhibition in both glutamine and mitochondrial metabolism, which in turn suppresses the PDAC growth both in vitro and in vivo. High basal levels of autophagy are critical for pancreatic cancer growth. The TFEB knockdown had no significant effect on the autophagic flux under normal conditions but interestingly caused a profound reduction in glutaminase (GLS) transcription, leading to an inhibition of glutamine metabolism. We observed that the direct binding of TFEB to the GLS and TFEB gene promotors regulates the transcription of GLS. We also found that the glutamate supplementation leads to a significant recovery of the PDAC growth that had been reduced by a TFEB knockdown. Taken together, our current data demonstrate that TFEB supports the PDAC cell growth by regulating glutaminase-mediated glutamine metabolism.
    Keywords:  GLS; PDAC; TFEB; glutamine
    DOI:  https://doi.org/10.3390/cancers13030483
  14. Autophagy. 2021 Jan 28. 1-15
    The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit selective autophagy.
    Päivi Ylä-Anttila, Soham Gupta, Maria G Masucci.
      Macroautophagy/autophagy plays an important role in the control of viral infections and viruses have evolved multiple strategies to interfere with autophagy to avoid destruction and promote their own replication and spread. Here we report that the deubiquitinase encoded in the N-terminal domain of the Epstein-Barr virus (EBV) large tegument protein, BPLF1, regulates selective autophagy. Mass spectrometry analysis identified several vesicular traffic and autophagy related proteins as BPLF1 interactors and potential substrates, suggesting that the viral protein targets this cellular defense during productive infection. Direct binding of BPLF1 to the autophagy receptor SQSTM1/p62 (sequestosome 1) was confirmed by co-immunoprecipitation of transfected BPLF1 and by in vitro affinity isolation of bacterially expressed proteins. Expression of the catalytically active BPLF1 was associated with decreased SQSTM1/p62 ubiquitination and failure to recruit LC3 to SQSTM1/p62-positive aggregates. Selective autophagy was inhibited as illustrated by the accumulation of large protein aggregates in BPLF1-positive cells co-transfected with an aggregate-prone HTT (huntingtin)-Q109 construct, and by a slower autophagy-dependent clearance of protein aggregates upon transfection of BPLF1 in cells expressing a tetracycline-regulated HTT-Q103. The inhibition of aggregate clearance was restored by overexpression of a SQSTM1/p62[E409A,K420R] mutant that does not require ubiquitination of Lys420 for cargo loading. These findings highlight a previously unrecognized role of the viral deubiquitinase in the regulation of selective autophagy, which may promote infection and the production of infectious virus. Abbreviations: BPLF1, BamH1 fragment left open reading frame-1; EBV, Epstein-Barr virus; GFP, green fluorescent protein; HTT, huntingtin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; PB1, Phox and Bem1 domain; PE, phosphatidylethanolamine; SQSTM1/p62, sequestosome 1; UBA, ubiquitin-associated domain.
    Keywords:  Autophagy; EBV; SQSTM1/p62; deubiquitinase; large tegument protein
    DOI:  https://doi.org/10.1080/15548627.2021.1874660
  15. J Cell Mol Med. 2021 Jan 29.
    Basic fibroblast growth factor accelerates myelin debris clearance through activating autophagy to facilitate early peripheral nerve regeneration.
    Yongsheng Jiang, Jiahong Liang, Rui Li, Yan Peng, JiangLi Huang, Lijiang Huang.
      The successful removal of damaged myelin sheaths during Wallerian degeneration (WD) is essential for ensuring structural remodelling and functional recovery following traumatic peripheral nerve injury (PNI). Recent studies have established that autophagy involves myelin phagocytosis and cellular homoeostasis, and its disorder impairs myelin clearance. Based on the role of basic fibroblast growth factor (bFGF) on exerting neuroprotection and angiogenesis during nerve tissue regeneration, we now explicitly focus on the issue about whether the therapeutic effect of bFGF on supporting nerve regeneration is closely related to accelerate the autophagic clearance of myelin debris during WD. Using sciatic nerve crushed model, we found that bFGF remarkedly improved axonal outgrowth and nerve reconstruction at the early phase of PNI (14 days after PNI). More importantly, we further observed that bFGF could enhance phagocytic capacity of Schwann cells (SCs) to engulf myelin debris. Additionally, this enhancing effect is accomplished by autophagy activation and the increase of autophagy flux by immunoblotting and immune-histochemical analyses. Taken together, our data suggest that the action of bFGF on modulating early peripheral nerve regeneration is closely associated with myelin debris removal by SCs, which might result in SC-mediated autophagy activation, highlighting its insight molecular mechanism as a neuroprotective agent for repairing PNI.
    Keywords:  autophagy; basic fibroblast growth factor; myelin clearance; peripheral nerve regrowth
    DOI:  https://doi.org/10.1111/jcmm.16274
  16. Antioxidants (Basel). 2021 Jan 20. pii: E149. [Epub ahead of print]10(2):
    Urban Aerosol Particulate Matter Promotes Necrosis and Autophagy via Reactive Oxygen Species-Mediated Cellular Disorders that are Accompanied by Cell Cycle Arrest in Retinal Pigment Epithelial Cells.
    Hyesook Lee, Da Hye Kim, Jeong-Hwan Kim, Seh-Kwang Park, Ji-Won Jeong, Mi-Young Kim, Seok-Ho Hong, Kyoung Seob Song, Gi-Young Kim, Jin Won Hyun, Yung Hyun Choi.
      Urban particulate matter (UPM) is recognized as a grave public health problem worldwide. Although a few studies have linked UPM to ocular surface diseases, few studies have reported on retinal dysfunction. Thus, the aim of the present study was to evaluate the influence of UPM on the retina and identify the main mechanism of UPM toxicity. In this study, we found that UPM significantly induced cytotoxicity with morphological changes in ARPE-19 human retinal pigment epithelial (RPE) cells and increased necrosis and autophagy but not apoptosis. Furthermore, UPM significantly increased G2/M arrest and simultaneously induced alterations in cell cycle regulators. In addition, DNA damage and mitochondrial dysfunction were remarkably enhanced by UPM. However, the pretreatment with the potent reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) effectively suppressed UPM-mediated cytotoxicity, necrosis, autophagy, and cell cycle arrest. Moreover, NAC markedly restored UPM-induced DNA damage and mitochondrial dysfunction. Meanwhile, UPM increased the expression of mitophagy-regulated proteins, but NAC had no effect on mitophagy. Taken together, although further studies are needed to identify the role of mitophagy in UPM-induced RPE injury, the present study provides the first evidence that ROS-mediated cellular damage through necrosis and autophagy is one of the mechanisms of UPM-induced retinal disorders.
    Keywords:  mitophagy; necrosis; reactive oxygen species (ROS); retinal pigment epithelial (RPE) cells; urban aerosol particulate matter (UPM)
    DOI:  https://doi.org/10.3390/antiox10020149
  17. J Mol Biol. 2021 Jan 20. pii: S0022-2836(21)00003-6. [Epub ahead of print] 166809
    Membrane binding and homodimerization of Atg16 via two distinct protein regions is essential for autophagy in yeast.
    Hana Popelka, Erin F Reinhart, Shree Padma Metur, Kelsie A Leary, Michael J Ragusa, Daniel J Klionsky.
      Macroautophagy is a bulk degradation mechanism in eukaryotic cells. Efficiency of an essential step of this process in yeast, Atg8 lipidation, relies on the presence of Atg16, a subunit of the Atg12-Atg5-Atg16 complex acting as the E3-like enzyme in the ubiquitination-like reaction. A current view on the functional structure of Atg16 in the yeast S. cerevisiae comes from the two crystal structures that reveal the Atg5-interacting α-helix linked via a flexible linker to an α-helix that assembles into a homodimer. This view does not explain the results of previous in vitro studies revealing Atg16-dependent deformations of membranes and liposome-binding of the Atg12-Atg5 conjugate upon addition of Atg16. Here we show that Atg16 acts as both a homodimerizing and peripheral membrane-binding polypeptide. These two characteristics are imposed by the two distinct regions that are disordered in the nascent protein. Atg16 binds to membranes in vivo via the amphipathic α-helix (amino acid residues 113-131) that has a coiled-coil-like propensity and a strong hydrophobic face for insertion into the membrane. The other protein region (residues 64-99) possesses a coiled-coil propensity, but not amphipathicity, and is dispensable for membrane anchoring of Atg16. This region acts as a Leu-zipper essential for formation of the Atg16 homodimer. Mutagenic disruption in either of these two distinct domains renders Atg16 proteins that, in contrast to wild type, completely fail to rescue the autophagy-defective phenotype of atg16Δ cells. Together, the results of this study yield a model for the molecular mechanism of Atg16 function in macroautophagy.
    Keywords:  amphipathic helix; coiled-coil; liposome sedimentation; protein intrinsic disorder; subcellular fractionation
    DOI:  https://doi.org/10.1016/j.jmb.2021.166809
  18. J Biol Chem. 2021 Jan 23. pii: S0021-9258(21)00106-X. [Epub ahead of print] 100335
    Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling.
    Akinori Eiyama, Mari J Aaltonen, Hendrik Nolte, Takashi Tatsuta, Thomas Langer.
      Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle phosphatidic acid (PA) mainly synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the cardiolipin synthase Crd1, Ups1 deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1Δ cells leads to altered unfolded protein response (UPR) and mTORC1 signaling, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine (PC) and a reduced phosphatidylethanolamine (PE)/PC ratio in the ER of ups1Δ cells which suppresses the UPR. Moreover, we observed inhibition of TORC1 signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the SEACIT complex, increased cytosolic protein synthesis and restored glycolytic growth of ups1Δ cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.
    Keywords:  Mitochondria; PRELID1; TORC1; Ups1; endoplasmic reticulum (ER); lipid transfer; phospholipid; unfolded protein response (UPR); yeast
    DOI:  https://doi.org/10.1016/j.jbc.2021.100335
  19. Biochem Pharmacol. 2021 Jan 26. pii: S0006-2952(21)00023-X. [Epub ahead of print] 114427
    Optineurin deletion disrupts metabotropic glutamate receptor 5-mediated regulation of ERK1/2, GSK3β/ZBTB16, mTOR/ULK1 signaling in autophagy.
    Karim S Ibrahim, Caitlyn J McLaren, Khaled S Abd-Elrahman, Stephen S G Ferguson.
      Optineurin (OPTN) is a multifunctional protein that mediates a network of cellular processes regulating membrane trafficking, inflammatory responses and autophagy. The OPTN-rich interactome includes Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gαq/11 protein receptor family. Recent evidence has shown that mGluR5, in addition to its canonical Gαq/11 protein-coupled signaling, regulates autophagic machinery via mTOR/ULK1 and GSK3β/ZBTB16 pathways in both Alzheimer's and Huntington's disease mouse models. Despite its potential involvement, the role of OPTN in mediating mGluR5 downstream signaling cascades remains largely unknown. Here, we employed a CRISPR/Cas9 OPTN-deficient STHdhQ7/Q7 striatal cell line and global OPTN knockout mice to investigate whether Optn gene deletion alters both mGluR5 canonical and noncanonical signaling. We find that OPTN is required for mGluR5-activated Ca2+ flux and ERK1/2 signaling following receptor activation in STHdhQ7/Q7 cells and acute hippocampal slices. Deletion of OPTN impairs both GSK3β/ZBTB16 and mTOR/ULK1 autophagic signaling in STHdhQ7/Q7 cells. Furthermore, mGluR5-dependent regulation of GSK3β/ZBTB16 and mTOR/ULK-1 autophagic signaling is impaired in hippocampal slices of OPTN knockout mice. Overall, we show that the crosstalk between OPTN and mGluR5 can have major implication on receptor signaling and therefore potentially contribute to the pathophysiology of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Autophagy; Ca(2+); GPCR; Optineurin; mGluR5
    DOI:  https://doi.org/10.1016/j.bcp.2021.114427
  20. iScience. 2021 Jan 22. 24(1): 102029
    Mitophagy of polarized sperm-derived mitochondria after fertilization.
    Karinna Rubio-Peña, Sara Al Rawi, Fanny Husson, France Lam, Jorge Merlet, Vincent Galy.
      Loss of membrane potential of sperm mitochondria has been regarded as the first step preceding mitophagy degradation after their entry into the C. elegans oocyte at fertilization. This is in line with the classical view of mitophagy of defective or abnormal mitochondria and could serve as a recognition signal for their specific and quick autophagy degradation. Here, using TMRE (tetramethylrhodamine ethyl ester) and live imaging we show that this is not the case. Instead, sperm inherited mitochondria show a stable labeling with TMRE before and at the time of autophagosomes formation. Interestingly, this labeling remains in late-stage-embryos of autophagy-defective-mutants suggesting that the loss of membrane potential occurs upon the entry of the mitochondria into the autophagy pathway. These stabilized and still polarized sperm mitochondria remain distinct but associated with the maternal-derived mitochondrial network suggesting a mechanism that prevents their fusion and represents an efficient additional protective system against fertilization-induced heteroplasmy.
    Keywords:  Cell Biology; Reproductive Medicine
    DOI:  https://doi.org/10.1016/j.isci.2020.102029
  21. Pharmaceutics. 2021 Jan 21. pii: 135. [Epub ahead of print]13(2):
    Lack of Autophagy Induction by Lithium Decreases Neuroprotective Effects in the Striatum of Aged Rats.
    Angelica Jardim Costa, Adolfo Garcia Erustes, Rita Sinigaglia, Carlos Eduardo Neves Girardi, Gustavo José da Silva Pereira, Rodrigo Portes Ureshino, Soraya Soubhi Smaili.
      The pharmacological modulation of autophagy is considered a promising neuroprotective strategy. While it has been postulated that lithium regulates this cellular process, the age-related effects have not been fully elucidated. Here, we evaluated lithium-mediated neuroprotective effects in young and aged striatum. After determining the optimal experimental conditions for inducing autophagy in loco with lithium carbonate (Li2CO3), we measured cell viability, reactive oxygen species (ROS) generation and oxygen consumption with rat brain striatal slices from young and aged animals. In the young striatum, Li2CO3 increased tissue viability and decreased ROS generation. These positive effects were accompanied by enhanced levels of LC3-II, LAMP 1, Ambra 1 and Beclin-1 expression. In the aged striatum, Li2CO3 reduced the autophagic flux and increased the basal oxygen consumption rate. Ultrastructural changes in the striatum of aged rats that consumed Li2CO3 for 30 days included electrondense mitochondria with disarranged cristae and reduced normal mitochondria and lysosomes area. Our data show that the striatum from younger animals benefits from lithium-mediated neuroprotection, while the striatum of older rats does not. These findings should be considered when developing neuroprotective strategies involving the induction of autophagy in aging.
    Keywords:  aging; autophagy; lithium; lysosome; mitochondria; striatum
    DOI:  https://doi.org/10.3390/pharmaceutics13020135
  22. Biofactors. 2021 Jan 26.
    Catalase deficiency induces reactive oxygen species mediated pexophagy and cell death in the liver during prolonged fasting.
    Raghbendra Kumar Dutta, Yunash Maharjan, Joon No Lee, Channy Park, Ye-Shih Ho, Raekil Park.
      Peroxisomes are dynamic organelles that participate in a diverse array of cellular processes, including β-oxidation, which produces a considerable amount of reactive oxygen species (ROS). Although we showed that catalase depletion induces ROS-mediated pexophagy in cells, the effect of catalase deficiency during conditions that favor ROS generation remains elusive in mice. In this study, we reported that prolonged fasting in catalase-knockout (KO) mice drastically increased ROS production, which induced liver-specific pexophagy, an autophagic degradation of peroxisomes. In addition, increased ROS generation induced the production of pro-inflammatory cytokines in the liver tissues of catalase-KO mice. Furthermore, there was a significant increase in the levels of aspartate transaminase and alanine transaminase as well as apparent cell death in the liver of catalase-KO mice during prolonged fasting. However, an intra-peritoneal injection of the antioxidant N-acetyl-l-cysteine (NAC) and autophagy inhibitor chloroquine inhibited the inflammatory response, liver damage, and pexophagy in the liver of catalase-KO mice during prolonged fasting. Consistently, genetic ablation of autophagy, Atg5 led to suppression of pexophagy during catalase inhibition by 3-aminotriazole (3AT). Moreover, treatment with chloroquine also ameliorated the inflammatory response and cell death in embryonic fibroblast cells from catalase-KO mice. Taken together, our data suggest that ROS-mediated liver-specific pexophagy observed during prolonged fasting in catalase-KO mice may be responsible for the process associated with hepatic cell death.
    Keywords:  catalase; cell death; liver; pexophagy; reactive oxygen species
    DOI:  https://doi.org/10.1002/biof.1708
  23. Proc Natl Acad Sci U S A. 2021 Feb 02. pii: e2020478118. [Epub ahead of print]118(5):
    Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin.
    Tobias Wijshake, Zhongju Zou, Beibei Chen, Lin Zhong, Guanghua Xiao, Yang Xie, John G Doench, Lynda Bennett, Beth Levine.
      Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1-specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin-mediated tumor suppression in breast cancer cells.
    Keywords:  Beclin 1; E-cadherin; breast cancer
    DOI:  https://doi.org/10.1073/pnas.2020478118
  24. Front Neurosci. 2020 ;14 612757
    Defective Autophagy and Mitophagy in Aging and Alzheimer's Disease.
    Michael Tran, P Hemachandra Reddy.
      Aging is the time-dependent process that all living organisms go through characterized by declining physiological function due to alterations in metabolic and molecular pathways. Many decades of research have been devoted to uncovering the cellular changes and progression of aging and have revealed that not all organisms with the same chronological age exhibit the same age-related declines in physiological function. In assessing biological age, factors such as epigenetic changes, telomere length, oxidative damage, and mitochondrial dysfunction in rescue mechanisms such as autophagy all play major roles. Recent studies have focused on autophagy dysfunction in aging, particularly on mitophagy due to its major role in energy generation and reactive oxidative species generation of mitochondria. Mitophagy has been implicated in playing a role in the pathogenesis of many age-related diseases, including Alzheimer's disease (AD), Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The purpose of our article is to highlight the mechanisms of autophagy and mitophagy and how defects in these pathways contribute to the physiological markers of aging and AD. This article also discusses how mitochondrial dysfunction, abnormal mitochondrial dynamics, impaired biogenesis, and defective mitophagy are related to aging and AD progression. This article highlights recent studies of amyloid beta and phosphorylated tau in relation to autophagy and mitophagy in AD.
    Keywords:  Alzheimer’s disease; aging; autophagy; mitochondria reactive oxygen species; mitophagy
    DOI:  https://doi.org/10.3389/fnins.2020.612757
  25. Nat Cell Biol. 2021 Jan 25.
    Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition.
    Carles Recasens-Alvarez, Cyrille Alexandre, Joanna Kirkpatrick, Hisashi Nojima, David J Huels, Ambrosius P Snijders, Jean-Paul Vincent.
      Ribosomes are multicomponent molecular machines that synthesize all of the proteins of living cells. Most of the genes that encode the protein components of ribosomes are therefore essential. A reduction in gene dosage is often viable albeit deleterious and is associated with human syndromes, which are collectively known as ribosomopathies1-3. The cell biological basis of these pathologies has remained unclear. Here, we model human ribosomopathies in Drosophila and find widespread apoptosis and cellular stress in the resulting animals. This is not caused by insufficient protein synthesis, as reasonably expected. Instead, ribosomal protein deficiency elicits proteotoxic stress, which we suggest is caused by the accumulation of misfolded proteins that overwhelm the protein degradation machinery. We find that dampening the integrated stress response4 or autophagy increases the harm inflicted by ribosomal protein deficiency, suggesting that these activities could be cytoprotective. Inhibition of TOR activity-which decreases ribosomal protein production, slows down protein synthesis and stimulates autophagy5-reduces proteotoxic stress in our ribosomopathy model. Interventions that stimulate autophagy, combined with means of boosting protein quality control, could form the basis of a therapeutic strategy for this class of diseases.
    DOI:  https://doi.org/10.1038/s41556-020-00626-1
  26. Adv Protein Chem Struct Biol. 2021 ;pii: S1876-1623(19)30097-5. [Epub ahead of print]123 73-93
    Autophagy proteins and its homeostasis in cellular environment.
    Vrushali Guhe, Bhavnita Soni, Prajakta Ingale, Shailza Singh.
      Autophagy is a self-destructing mechanism of cell via lysosomal degradation, which helps to degrade/destroy hazardous substances, proteins, degenerating organelles and recycling nutrients. It plays an important role is cellular homeostasis and regulates internal environment of cell, moreover, when needed causes non-apoptotic programmed death of cell. Autophagy has been observed as one of the major factors in parasite clearance in leishmaniasis. Being an intra-cellular pathogen, the cell mediated response is the only alternative for adaptive immunity against Leishmania in host. Pro-inflammatory cytokines IL12 and TNFα generate Th2 response which helps in active phagocytosis of parasite whereas an anti-inflammatory cytokine like IL10 mediate parasite promotion by blocking autophagic pathways and inhibiting phagocytic actions. In the present chapter, through systems biology approach, we are trying to decipher the role of pro-inflammatory and anti-inflammatory cytokine in autophagy during leishmanial infection. TLR2/6 mediated signaling stimulated by LPG produces many pro-inflammatory cytokines like IL12, TNFα and IL6 etc. Among them TNFα, causes the activation of PI3P through a series of events, which results in activation of autophagic machinery, whereas, IL10 through ATG9 and mTOR activation, inhibits autophagy. The mathematical modeling of these pathways shows that, ATG9-PI3P act as a negative feedback loop in autophagic machinery of leishmaniasis.
    Keywords:  Atg9; Autophagy; IL10; Leishmaniasis; TNFα
    DOI:  https://doi.org/10.1016/bs.apcsb.2019.12.002
  27. Biogerontology. 2021 Jan 27.
    Aging and age-related diseases: from mechanisms to therapeutic strategies.
    Zhe Li, Zhenkun Zhang, Yikun Ren, Yingying Wang, Jiarui Fang, Han Yue, Shanshan Ma, Fangxia Guan.
      Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.
    Keywords:  Age‐related diseases; Aging; Anti‐aging drugs; Hallmarks of aging
    DOI:  https://doi.org/10.1007/s10522-021-09910-5
  28. Front Cell Dev Biol. 2020 ;8 609683
    MiT/TFE Family of Transcription Factors: An Evolutionary Perspective.
    Martina La Spina, Pablo S Contreras, Alberto Rissone, Naresh K Meena, Eutteum Jeong, José A Martina.
      Response and adaptation to stress are critical for the survival of all living organisms. The regulation of the transcriptional machinery is an important aspect of these complex processes. The members of the microphthalmia (MiT/TFE) family of transcription factors, apart from their involvement in melanocyte biology, are emerging as key players in a wide range of cellular functions in response to a plethora of internal and external stresses. The MiT/TFE proteins are structurally related and conserved through evolution. Their tissue expression and activities are highly regulated by alternative splicing, promoter usage, and posttranslational modifications. Here, we summarize the functions of MiT/TFE proteins as master transcriptional regulators across evolution and discuss the contribution of animal models to our understanding of the various roles of these transcription factors. We also highlight the importance of deciphering transcriptional regulatory mechanisms in the quest for potential therapeutic targets for human diseases, such as lysosomal storage disorders, neurodegeneration, and cancer.
    Keywords:  autophagy; evolution; helix-loop-helix transcription factor 30 (HLH-30); lysosomes; mammalian target of rapamycin (mTOR); microphthalmia-associated transcription factor (MITF); transcription factor E3 (TFE3); transcription factor EB (TFEB)
    DOI:  https://doi.org/10.3389/fcell.2020.609683
  29. Neurosci Biobehav Rev. 2021 Jan 23. pii: S0149-7634(21)00030-0. [Epub ahead of print]
    Autophagy status as a gateway for stress-induced catecholamine interplay in neurodegeneration.
    Francesco Fornai, Stefano Puglisi-Allegra.
      The catecholamine-containing brainstem nuclei locus coeruleus (LC) and ventral tegmental area (VTA) are critically involved in stress responses. Alterations of catecholamine systems during chronic stress may contribute to neurodegeneration, including cognitive decline. Stress-related catecholamine alterations, while contributing to anxiety and depression, might accelerate neuronal degeneration by increasing the formation of toxic dopamine and norepinephrine by-products. These, in turn, may impair proteostasis within a variety of cortical and subcortical areas. In particular, the molecular events governing neurotransmission, neuroplasticity, and proteostasis within LC and VTA affect a variety of brain areas. Therefore, we focus on alterations of autophagy machinery in these nuclei as a relevant trigger in this chain of events. In fact, these catecholamine-containing areas are mostly prone to autophagy-dependent neurodegeneration. Thus, we propose a dynamic hypothesis according to which stress-induced autophagy alterations within the LC-VTA network foster a cascade towards early neurodegeneration within these nuclei.
    Keywords:  Autophagy; Dopamine; Glutamate; Locus coeruleus; Neurodegeneration; Norepinephrine; Stress; Ventral tegmental Area
    DOI:  https://doi.org/10.1016/j.neubiorev.2021.01.015
  30. Front Cell Dev Biol. 2020 ;8 614178
    Autophagy and Exosomes Relationship in Cancer: Friends or Foes?
    Marta Colletti, Donatella Ceglie, Angela Di Giannatale, Francesca Nazio.
      Autophagy is an intracellular degradation process involved in the removal of proteins and damaged organelles by the formation of a double-membrane vesicle named autophagosome and degraded through fusion with lysosomes. An intricate relationship between autophagy and the endosomal and exosomal pathways can occur at different stages with important implications for normal physiology and human diseases. Recent researches have revealed that extracellular vesicles (EVs), such as exosomes, could have a cytoprotective role by inducing intracellular autophagy; on the other hand, autophagy plays a crucial role in the biogenesis and degradation of exosomes. Although the importance of these processes in cancer is well established, their interplay in tumor is only beginning to be documented. In some tumor contexts (1) autophagy and exosome-mediated release are coordinately activated, sharing the molecular machinery and regulatory mechanisms; (2) cancer cell-released exosomes impact on autophagy in recipient cells through mechanisms yet to be determined; (3) exosome-autophagy relationship could affect drug resistance and tumor microenvironment (TME). In this review, we survey emerging discoveries relevant to the exosomes and autophagy crosstalk in the context of cancer initiation, progression and recurrence. Consequently, we discuss clinical implications by targeting autophagy-exosomal pathway interaction and how this could lay a basis for the purpose of novel cancer therapeutics.
    Keywords:  autophagy; cancer; exosome; microenvironment; target therapy
    DOI:  https://doi.org/10.3389/fcell.2020.614178
  31. Cardiovasc Res. 2021 Jan 29. pii: cvab033. [Epub ahead of print]
    The complex network of mTOR signaling in the heart.
    Sebastiano Sciarretta, Maurizio Forte, Giacomo Frati, Junichi Sadoshima.
      The mechanistic target of rapamycin (mTOR) integrates several intracellular and extracellular signals involved in the regulation of anabolic and catabolic processes. mTOR assembles into two macromolecular complexes, named mTORC1 and mTORC2, which have different regulators, substrates and functions. Studies of gain- and loss-of-function animal models of mTOR signaling revealed that mTORC1/2 elicit both adaptive and maladaptive functions in the cardiovascular system. Both mTORC1 and mTORC2 are indispensable for driving cardiac development and cardiac adaption to stress, such as pressure overload. However, persistent and deregulated mTORC1 activation in the heart is detrimental during stress and contributes to the development and progression of cardiac remodeling and genetic and metabolic cardiomyopathies. In this review, we discuss the latest findings regarding the role of mTOR in the cardiovascular system, both under basal conditions and during stress, such as pressure overload, ischemia and metabolic stress. Current data suggest that mTOR modulation may represent a potential therapeutic strategy for the treatment of cardiac diseases.
    Keywords:  heart disease; mTOR; mTORC1; mTORC2; rapamycin
    DOI:  https://doi.org/10.1093/cvr/cvab033
  32. Nat Rev Mol Cell Biol. 2021 Jan 28.
    Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing.
    Simon Alberti, Anthony A Hyman.
      Biomolecular condensates are membraneless intracellular assemblies that often form via liquid-liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.
    DOI:  https://doi.org/10.1038/s41580-020-00326-6
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