bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2021–04–04
eleven papers selected by
Su Hyun Lee, Seoul National University
  1. The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore.
  2. TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy.
  3. ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system.
  4. ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.
  5. TRIM28 functions as a negative regulator of aggresome formation.
  6. Autophagy is a double-edged sword in the therapy of colorectal cancer.
  7. Emerging Views of OPTN (optineurin) Function in the Autophagic Process Associated with Disease.
  8. Autophagosome content profiling reveals receptor-specific cargo candidates.
  9. Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth.
  10. Amino Acid Depletion Therapies: Starving Cancer Cells to Death.
  11. Pivotal role of endothelial cell autophagy in sepsis.
  1. Autophagy. 2021 Mar 30. 1-15
    The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore.
    Hao-Chun Chang, Ran N Tao, Chong Teik Tan, Ya Jun Wu, Boon Huat Bay, Victor C Yu.
      MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.
    Keywords:  Autophagosome formation; LC3-binding protein; LIR motif; autophagy; cell death; nutrient deprivation
    DOI:  https://doi.org/10.1080/15548627.2021.1896157
  2. Autophagy. 2021 Mar 28. 1-18
    TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy.
    Wenxian Wu, Xiaojing Wang, Yadong Sun, Niklas Berleth, Jana Deitersen, David Schlütermann, Fabian Stuhldreier, Nora Wallot-Hieke, María José Mendiburo, Jan Cox, Christoph Peter, Ann Kathrin Bergmann, Björn Stork.
      Macroautophagy/autophagy and necroptosis represent two opposing cellular s tress responses. Whereas autophagy primarily fulfills a cyto-protective function, necroptosis is a form of regulated cell death induced via death receptors. Here, we aimed at investigating the molecular crosstalk between these two pathways. We observed that RIPK3 directly associates with AMPK and phosphorylates its catalytic subunit PRKAA1/2 at T183/T172. Activated AMPK then phosphorylates the autophagy-regulating proteins ULK1 and BECN1. However, the lysosomal degradation of autophagosomes is blocked by TNF-induced necroptosis. Specifically, we observed dysregulated SNARE complexes upon TNF treatment; e.g., reduced levels of full-length STX17. In summary, we identified RIPK3 as an AMPK-activating kinase and thus a direct link between autophagy- and necroptosis-regulating kinases.Abbreviations ACACA/ACC: acetyl-CoA carboxylase alpha; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BECN1: beclin 1; GFP: green fluorescent protein; EBSS: Earle's balanced salt solution; Hs: Homo sapiens; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain like pseudokinase; Mm: Mus musculus; MTOR: mechanistic target of rapamycin kinase; MVB: multivesicular body; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PLA: proximity ligation assay; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKAA2: protein kinase AMP-activated catalytic subunit alpha 2; PRKAB2: protein kinase AMP-activated non-catalytic subunit beta 2; PRKAG1: protein kinase AMP-activated non-catalytic subunit gamma 1; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; STX7: syntaxin 7; STX17: syntaxin 17; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; VAMP8: vesicle associated membrane protein 8; WT: wild-type.
    Keywords:  AMPK; RIPK3; STX17; autophagy; necroptosis
    DOI:  https://doi.org/10.1080/15548627.2021.1899667
  3. Mol Cell. 2021 Mar 25. pii: S1097-2765(21)00169-6. [Epub ahead of print]
    ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system.
    Thanh Ngoc Nguyen, Benjamin Scott Padman, Susanne Zellner, Grace Khuu, Louise Uoselis, Wai Kit Lam, Marvin Skulsuppaisarn, Runa S J Lindblom, Emily M Watts, Christian Behrends, Michael Lazarou.
      The sequestration of damaged mitochondria within double-membrane structures termed autophagosomes is a key step of PINK1/Parkin mitophagy. The ATG4 family of proteases are thought to regulate autophagosome formation exclusively by processing the ubiquitin-like ATG8 family (LC3/GABARAPs). We discover that human ATG4s promote autophagosome formation independently of their protease activity and of ATG8 family processing. ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. Artificial intelligence-directed 3D electron microscopy of phagophores shows that ATG4s promote phagophore-ER contacts during the lipid-transfer phase of autophagosome formation. We also show that ATG8 removal during autophagosome maturation does not depend on ATG4 activity. Instead, ATG4s can disassemble ATG8-protein conjugates, revealing a role for ATG4s as deubiquitinating-like enzymes. These findings establish non-canonical roles of the ATG4 family beyond the ATG8 lipidation axis and provide an AI-driven framework for rapid 3D electron microscopy.
    Keywords:  ATG4; ATG9a; FIB-SEM; LRBA; PINK1; Parkin; autophagosome; autophagy; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.molcel.2021.03.001
  4. Autophagy. 2021 Apr 02.
    ATG14 and RB1CC1 play essential roles in maintaining muscle homeostasis.
    Dongfang Li, Peter Vogel, Xiujie Li-Harms, Bo Wang, Mondira Kundu.
      Defects in macroautophagy/autophagy are implicated in the pathogenesis of neuromuscular and heart diseases. To precisely define the roles of autophagy-related genes in skeletal and cardiac muscles, we generated muscle-specific rb1cc1- and atg14-conditional knockout (cKO) mice by using Ckm/Ckmm2-Cre and compared their phenotypes to those of ulk1 ulk2-conditional double-knockout (cDKO) mice. atg14-cKO mice developed hypertrophic cardiomyopathy, which was associated with abnormal accumulation of autophagic cargoes in the heart and early mortality. Skeletal muscles of both atg14-cKO and rb1cc1-cKO mice showed features of autophagic vacuolar myopathy with ubiquitin+ SQSTM1+ deposits, but only those of rb1cc1-cKO mice showed TARDBP/TDP-43+ pathology and other features of the inclusion body myopathy-like disease we previously described in ulk1 ulk2-cDKO mice. Herein, we highlight tissue-specific differences between skeletal and cardiac muscles in their reliance on core autophagy proteins and unique roles for ULK1-ULK2 and RB1CC1 among these proteins in the development of TARDBP+ pathology.
    Keywords:  ATG14; RB1CC1; RNA-binding protein; ULK1; ULK2; autophagic vacuolar myopathy; autophagy; cardiomyopathy; inclusion body myopathy
    DOI:  https://doi.org/10.1080/15548627.2021.1911549
  5. Autophagy. 2021 Mar 30.
    TRIM28 functions as a negative regulator of aggresome formation.
    Jeeyoon Chang, Hyun Jung Hwang, Byungju Kim, Yeon-Gil Choi, Joori Park, Yeonkyoung Park, Ban Seok Lee, Heedo Park, Min Ji Yoon, Jae-Sung Woo, Chungho Kim, Man-Seong Park, Jong-Bong Lee, Yoon Ki Kim.
      Selective recognition and elimination of misfolded polypeptides are crucial for protein homeostasis. When the ubiquitin-proteasome system is impaired, misfolded polypeptides tend to form small cytosolic aggregates and are transported to the aggresome and eventually eliminated by the autophagy pathway. Despite the importance of this process, the regulation of aggresome formation remains poorly understood. Here, we identify TRIM28/TIF1β/KAP1 (tripartite motif containing 28) as a negative regulator of aggresome formation. Direct interaction between TRIM28 and CTIF (cap binding complex dependent translation initiation factor) leads to inefficient aggresomal targeting of misfolded polypeptides. We also find that either treatment of cells with poly I:C or infection of the cells by influenza A viruses triggers the phosphorylation of TRIM28 at S473 in a way that depends on double-stranded RNA-activated protein kinase. The phosphorylation promotes association of TRIM28 with CTIF, inhibits aggresome formation, and consequently suppresses viral proliferation. Collectively, our data provide compelling evidence that TRIM28 is a negative regulator of aggresome formation.
    Keywords:  CTIF; DCTN1; EEF1A1; EIF2AK2; aggrephagy; influenza A virus
    DOI:  https://doi.org/10.1080/15548627.2021.1909835
  6. Oncol Lett. 2021 May;21(5): 378
    Autophagy is a double-edged sword in the therapy of colorectal cancer.
    Bo Zhang, Lantao Liu.
      Colorectal cancer is one of the leading causes of cancer-associated mortality worldwide. The limitations of colorectal cancer treatment include various types of multidrug resistance and the contingent damage to neighboring normal cells caused by chemotherapy. Macroautophagy/autophagy and apoptosis are essential mechanisms involved in cancer cell regulation of chemotherapy. Autophagy can either cause cancer cell death or promote tumor survival during colorectal cancer. Given that autophagy is involved in chemotherapy of colorectal cancer, an improved insight into the potential interactions between apoptosis and autophagy is crucial. The present review aimed to summarize the involvement of autophagy in the regulation of colorectal cancer and its association with chemotherapy. Furthermore, the role of natural product extraction, novel chemicals and small molecules, as well as radiation, which induce autophagy in colorectal cancer cells, were reviewed. Finally, the present review aimed to provide an outlook for the regulation of autophagy as a novel approach to the treatment of cancer, particularly chemotherapy-resistant colorectal cancer.
    Keywords:  Beclin 1; apoptosis; autophagy; chemotherapy; colorectal cancer
    DOI:  https://doi.org/10.3892/ol.2021.12639
  7. Autophagy. 2021 Mar 30.
    Emerging Views of OPTN (optineurin) Function in the Autophagic Process Associated with Disease.
    Yueping Qiu, Jincheng Wang, Hui Li, Bo Yang, Jiajia Wang, Qiaojun He, Qinjie Weng.
      Macroautophagy/autophagy is a highly conserved process in eukaryotic cells. It plays a critical role in cellular homeostasis by delivering cytoplasmic cargos to lysosomes for selective degradation. OPTN (optineurin), a well-recognized autophagy receptor, has received considerable attention due to its multiple roles in the autophagic process. OPTN is associated with many human disorders that are closely related to autophagy, such as rheumatoid arthritis, osteoporosis, and nephropathy. Here, we review the function of OPTN as an autophagy receptor at different stages of autophagy, focusing on cargo recognition, autophagosome formation, autophagosome maturation, and lysosomal quality control. OPTN tends to be protective in most autophagy associated diseases, though the molecular mechanism of OPTN regulation in these diseases is not well understood. A comprehensive review of the function of OPTN in autophagy provides valuable insight into the pathogenesis of human diseases related to OPTN and facilitates the discovery of potential key regulators and novel therapeutic targets for disease intervention in patients with autophagic diseases.
    Keywords:  autophagosome formation; autophagy; cargo recognition; diseases; lysosomal quality control; mitophagy; optineurin (OPTN)
    DOI:  https://doi.org/10.1080/15548627.2021.1908722
  8. Autophagy. 2021 Mar 28.
    Autophagosome content profiling reveals receptor-specific cargo candidates.
    Susanne Zellner, Christian Behrends.
      Selective autophagy receptors have been implicated in the degradation of cellular constituents of various size and rigidity. However, the identity of protein cargo have largely remained elusive. In our recent study, we combined limited proteolysis-enhanced proximity biotinylation and organelle enrichment with quantitative proteomics to map the inventory of autophagosomes in a manner dependent on six different selective autophagy receptors, namely SQSTM1/p62, NBR1, CALCOCO2/NDP52, OPTN, TAX1BP1 and TOLLIP. Conducting this approach under basal and proteostasis-challenged conditions in mammalian cells led to the identification of various new autophagy substrates of which some were degraded through endosomal microautophagy rather than canonical autophagy dependent on the receptors TOLLIP and SQSTM1, respectively.
    Keywords:  (5-6): Selective autophagy receptors; APEX2; TOLLIP; endosomal microautophagy; proteostasis challenges; proximity proteomics
    DOI:  https://doi.org/10.1080/15548627.2021.1909410
  9. Proc Natl Acad Sci U S A. 2021 Apr 06. pii: e2020215118. [Epub ahead of print]118(14):
    Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth.
    Zhiqiang Deng, Xianting Li, Marian Blanca Ramirez, Kerry Purtell, Insup Choi, Jia-Hong Lu, Qin Yu, Zhenyu Yue.
      Autophagy is a catabolic pathway that provides self-nourishment and maintenance of cellular homeostasis. Autophagy is a fundamental cell protection pathway through metabolic recycling of various intracellular cargos and supplying the breakdown products. Here, we report an autophagy function in governing cell protection during cellular response to energy crisis through cell metabolic rewiring. We observe a role of selective type of autophagy in direct activation of cyclic AMP protein kinase A (PKA) and rejuvenation of mitochondrial function. Mechanistically, autophagy selectively degrades the inhibitory subunit RI of PKA holoenzyme through A-kinase-anchoring protein (AKAP) 11. AKAP11 acts as an autophagy receptor that recruits RI to autophagosomes via LC3. Glucose starvation induces AKAP11-dependent degradation of RI, resulting in PKA activation that potentiates PKA-cAMP response element-binding signaling, mitochondria respiration, and ATP production in accordance with mitochondrial elongation. AKAP11 deficiency inhibits PKA activation and impairs cell survival upon glucose starvation. Our results thus expand the view of autophagy cytoprotection mechanism by demonstrating selective autophagy in RI degradation and PKA activation that fuels the mitochondrial metabolism and confers cell resistance to glucose deprivation implicated in tumor growth.
    Keywords:  AKAP11; PKA; autophagy; cell survival; mitochondrial metabolism
    DOI:  https://doi.org/10.1073/pnas.2020215118
  10. Trends Endocrinol Metab. 2021 Mar 29. pii: S1043-2760(21)00049-7. [Epub ahead of print]
    Amino Acid Depletion Therapies: Starving Cancer Cells to Death.
    Miriam Butler, Laurens T van der Meer, Frank N van Leeuwen.
      Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers as well as mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand for biomass accumulation and energy production and to maintain redox homeostasis, tumor cells undergo profound changes in their metabolism. In addition to the diversion of glucose metabolism, this is achieved by upregulation of amino acid metabolism. Interfering with amino acid availability can be selectively lethal to tumor cells and has proven to be a cancer specific Achilles' heel. Here we review the biology behind such cancer specific amino acid dependencies and discuss how these vulnerabilities can be exploited to improve cancer therapies.
    Keywords:  amino acid depletion therapy; amino acid metabolism; cancer; tumor metabolism
    DOI:  https://doi.org/10.1016/j.tem.2021.03.003
  11. Life Sci. 2021 Mar 29. pii: S0024-3205(21)00398-2. [Epub ahead of print] 119413
    Pivotal role of endothelial cell autophagy in sepsis.
    Yuexian Li, Liangyuan Suo, Zhiling Fu, Guoqing Li, Jin Zhang.
      Sepsis is a fatal organ dysfunction resulting from a disordered host response to infection. Endothelial cells (ECs) are usually the primary targets of inflammatory mediators in sepsis; damage to ECs plays a pivotal part in vital organ failure. In recent studies, autophagy was suggested to play a critical role in the ECs injury although the mechanisms by which ECs are injured in sepsis are not well elucidated. Autophagy is a highly conserved catabolic process that includes sequestrating plasma contents and transporting cargo to lysosomes for recycling the vital substrates required for metabolism. This pathway also counteracts microbial invasion to balance and retain homeostasis, especially during sepsis. Increasing evidence indicates that autophagy is closely associated with endothelial function. The role of autophagy in sepsis may or may not be favorable depending upon conditions. In the present review, the current knowledge of autophagy in the process of sepsis and its influence on ECs was evaluated. In addition, the potential of targeting EC autophagy for clinical treatment of sepsis was discussed.
    Keywords:  Apoptosis; Autophagy; Endothelial cells; Hemostasis; Inflammation; Mitophagy; Sepsis
    DOI:  https://doi.org/10.1016/j.lfs.2021.119413
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