bims-apauto Biomed News
on Apoptosis and autophagy
Issue of 2021‒03‒21
ten papers selected by
Su Hyun Lee
Seoul National University
  1. Mitophagy in Pancreatic Cancer.
  2. A Guide To… The Regulation Of Selective Autophagy Receptors.
  3. Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy.
  4. VCP/p97 modulates PtdIns3P production and autophagy initiation.
  5. AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3.
  6. Selective autophagy receptor SQSTM1/ p62 inhibits Seneca Valley virus replication by targeting viral VP1 and VP3.
  7. Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis.
  8. PKA compartmentalization links cAMP signaling and autophagy.
  9. The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro.
  10. Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies.
  1. Front Oncol. 2021 ;11 616079
    Mitophagy in Pancreatic Cancer.
    Yangchun Xie, Jiao Liu, Rui Kang, Daolin Tang.
      Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive solid malignancies, is characterized by the presence of oncogenic KRAS mutations, poor response to current therapies, prone to metastasis, and a low 5-year overall survival rate. Macroautophagy (herein referred to as autophagy) is a lysosome-dependent degradation system that forms a series of dynamic membrane structures to engulf, degrade, and recycle various cargoes, such as unused proteins, damaged organelles, and invading pathogens. Autophagy is usually upregulated in established cancers, but it plays a dual role in the regulation of the initiation and progression of PDAC. As a type of selective autophagy, mitophagy is a mitochondrial quality control mechanism that uses ubiquitin-dependent (e.g., the PINK1-PRKN pathway) and -independent (e.g., BNIP3L/NIX, FUNDC1, and BNIP3) pathways to regulate mitochondrial turnover and participate in the modulation of metabolism and cell death. Genetically engineered mouse models indicate that the loss of PINK1 or PRKN promotes, whereas the depletion of BNIP3L inhibits oncogenic KRAS-driven pancreatic tumorigenesis. Mitophagy also play a dual role in the regulation of the anticancer activity of certain cytotoxic agents (e.g., rocaglamide A, dichloroacetate, fisetin, and P. suffruticosa extracts) in PDAC cells or xenograft models. In this min-review, we summarize the latest advances in understanding the complex role of mitophagy in the occurrence and treatment of PDAC.
    Keywords:  PDAC - pancreatic ductal adenocarcinoma; autophagy; mitophagy; therapy; tumorigenesis
    DOI:  https://doi.org/10.3389/fonc.2021.616079
  2. FEBS J. 2021 Mar 17.
    A Guide To… The Regulation Of Selective Autophagy Receptors.
    A Gubas, I Dikic.
      Autophagy is a highly conserved catabolic process cells use to maintain their homeostasis by degrading misfolded, damaged, and excessive proteins, non-functional organelles, foreign pathogens, and other cellular components. Hence, autophagy can be non-selective, where bulky portions of the cytoplasm are degraded upon stress, or a highly selective process, where pre-selected cellular components are degraded. To distinguish between different cellular components, autophagy employs selective autophagy receptors, which will link the cargo to the autophagy machinery, thereby sequestering it in the autophagosome for its subsequent degradation in the lysosome. Autophagy receptors undergo post-translational and structural modifications to fulfil their role in autophagy, or upon executing their role, for their own degradation. We highlight the four most prominent protein modifications - phosphorylation, ubiquitination, acetylation, and oligomerisation - that are essential for autophagy receptor recruitment, function, and turnover. Understanding the regulation of selective autophagy receptors will provide deeper insights into the pathway and open up potential therapeutic avenues.
    Keywords:  Autophagy; oligomerisation; phosphorylation; receptor; ubiquitination
    DOI:  https://doi.org/10.1111/febs.15824
  3. Cell Death Differ. 2021 Mar 15.
    Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy.
    Anthea Di Rita, Daniela F Angelini, Teresa Maiorino, Valerio Caputo, Raffaella Cascella, Mukesh Kumar, Matteo Tiberti, Matteo Lambrughi, Nicole Wesch, Frank Löhr, Volker Dötsch, Marianna Carinci, Pasquale D'Acunzo, Valerio Chiurchiù, Elena Papaleo, Vladimir V Rogov, Emiliano Giardina, Luca Battistini, Flavie Strappazzon.
      The role of mitophagy, a process that allows the removal of damaged mitochondria from cells, remains unknown in multiple sclerosis (MS), a disease that is found associated with dysfunctional mitochondria. Here we have qualitatively and quantitatively studied the main players in PINK1-mediated mitophagy in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting MS. We found the variant c.491G>A (rs550510, p.G140E) of NDP52, one of the major mitophagy receptor genes, associated with a MS cohort. Through the characterization of this variant, we discovered that the residue 140 of human NDP52 is a crucial modulator of NDP52/LC3C binding, promoting the formation of autophagosomes in order to drive efficient mitophagy. In addition, we found that in the PBMC population, NDP52 is mainly expressed in B cells and by ensuring efficient mitophagy, it is able to limit the production of the proinflammatory cytokine TNF-α following cell stimulation. In sum, our results contribute to a better understanding of the role of NDP52 in mitophagy and underline, for the first time, a possible role of NDP52 in MS.
    DOI:  https://doi.org/10.1038/s41418-021-00766-3
  4. Autophagy. 2021 Mar 09. 1-2
    VCP/p97 modulates PtdIns3P production and autophagy initiation.
    Lidia Wrobel, Sandra M Hill, Avraham Ashkenazi, David C Rubinsztein.
      VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex. Acute inhibition of VCP activity impairs autophagy induction, demonstrated by a diminished PtdIns3P production and decreased recruitment of early autophagy markers WIPI2 and ATG16L1. Thus, VCP promotes autophagosome biogenesis, in addition to its previously described role in autophagosome maturation.
    Keywords:  ATXN3; PI(3)P; PI3K; VCP/p97; autophagy initiation; beclin 1
    DOI:  https://doi.org/10.1080/15548627.2021.1898742
  5. Autophagy. 2021 Mar 18. 1-19
    AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3.
    Mathieu Paquette, Leeanna El-Houjeiri, Linda C Zirden, Pietri Puustinen, Paola Blanchette, Hyeonju Jeong, Kurt Dejgaard, Peter M Siegel, Arnim Pause.
      Increased macroautophagy/autophagy and lysosomal activity promote tumor growth, survival and chemo-resistance. During acute starvation, autophagy is rapidly engaged by AMPK (AMP-activated protein kinase) activation and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) inhibition to maintain energy homeostasis and cell survival. TFEB (transcription factor E3) and TFE3 (transcription factor binding to IGHM enhancer 3) are master transcriptional regulators of autophagy and lysosomal activity and their cytoplasm/nuclear shuttling is controlled by MTORC1-dependent multisite phosphorylation. However, it is not known whether and how the transcriptional activity of TFEB or TFE3 is regulated. We show that AMPK mediates phosphorylation of TFEB and TFE3 on three serine residues, leading to TFEB and TFE3 transcriptional activity upon nutrient starvation, FLCN (folliculin) depletion and pharmacological manipulation of MTORC1 or AMPK. Collectively, we show that MTORC1 specifically controls TFEB and TFE3 cytosolic retention, whereas AMPK is essential for TFEB and TFE3 transcriptional activity. This dual and opposing regulation of TFEB and TFE3 by MTORC1 and AMPK is reminiscent of the regulation of another critical regulator of autophagy, ULK1 (unc-51 like autophagy activating kinase 1). Surprisingly, we show that chemoresistance is mediated by AMPK-dependent activation of TFEB, which is abolished by pharmacological inhibition of AMPK or mutation of serine 466, 467 and 469 to alanine residues within TFEB. Altogether, we show that AMPK is a key regulator of TFEB and TFE3 transcriptional activity, and we validate AMPK as a promising target in cancer therapy to evade chemotherapeutic resistance.AbbreviationsACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: AMP-activated protein kinase; AMPKi: AMPK inhibitor, SBI-0206965; CA: constitutively active; CARM1: coactivator-associated arginine methyltransferase 1; CFP: cyan fluorescent protein; CLEAR: coordinated lysosomal expression and regulation; DKO: double knock-out; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; DQ-BSA: self-quenched BODIPY® dye conjugates of bovine serum albumin; EBSS: Earle's balanced salt solution; FLCN: folliculin; GFP: green fluorescent protein; GST: glutathione S-transferases; HD: Huntington disease; HTT: huntingtin; KO: knock-out; LAMP1: lysosomal associated membrane protein 1; MEF: mouse embryonic fibroblasts; MITF: melanocyte inducing transcription factor; MTORC1: MTOR complex 1; PolyQ: polyglutamine; RPS6: ribosomal protein S6; RT-qPCR: reverse transcription quantitative polymerase chain reaction; TCL: total cell lysates; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TKO: triple knock-out; ULK1: unc-51 like autophagy activating kinase 1.
    Keywords:  AMP-activated protein kinase; autophagy; drug resistance; lysosomal biogenesis; mechanistic target of rapamycin kinase; phosphorylation; transcription factor E3; transcription factor EB
    DOI:  https://doi.org/10.1080/15548627.2021.1898748
  6. Autophagy. 2021 Mar 14. 1-13
    Selective autophagy receptor SQSTM1/ p62 inhibits Seneca Valley virus replication by targeting viral VP1 and VP3.
    Wei Wen, Xiangmin Li, Mengge Yin, Haoyuan Wang, Liuxin Qin, Hui Li, Wenqiang Liu, Zekai Zhao, Qiongqiong Zhao, Huanchun Chen, Junjie Hu, Ping Qian.
      Macroautophagy/autophagy plays a critical role in antiviral immunity through targeting viruses and initiating host immune responses. The receptor protein, SQSTM1/p62 (sequestosome 1), plays a vital role in selective autophagy. It serves as a receptor targeting ubiquitinated proteins or pathogens to phagophores for degradation. In this study, we explored the reciprocal regulation between selective autophagy receptor SQSTM1 and Seneca Valley virus (SVV). SVV infection induced autophagy. Autophagy promoted SVV infection in pig cells but played opposite functions in human cells. Overexpression of SQSTM1 decreased viral protein production and reduced viral titers. Further study showed that SQSTM1 interacted with SVV VP1 and VP3 independent of its UBA domain. SQSTM1 targeted SVV VP1 and VP3 to phagophores for degradation to inhibit viral replication. To counteract this, SVV evolved strategies to circumvent the host autophagic machinery to promote viral replication. SVV 3Cpro targeted the receptor SQSTM1 for cleavage at glutamic acid 355, glutamine 392, and glutamine 395 and abolished its capacity to mediate selective autophagy. At the same time, the 3Cpro-mediated SQSTM1 cleavage products lost the ability to inhibit viral propagation. Collectively, our results provide evidence for selective autophagy in host against viruses and reveal potential viral strategies to evade autophagic machinery for successful pathogenesis. Abbreviations: Baf.A1: bafilomycin A1; Co-IP: co-immunoprecipitation; hpi: h post-infection; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MOI: multiplicity of infection; PB1: N-terminal Phox/Bem1p; Rap.: rapamycin; Seneca Valley virus: SVV; SQSTM1/p62: sequestosome 1; SQSTM1-N355: residues 1 to 355 of SQSTM1; SQSTM1-C355: residues 355 to 478 of SQSTM1; SQSTM1-N392: residues 1 to 392 of SQSTM1; SQSTM1-C392: residues 392 to 478 of SQSTM1; SQSTM1-N388: residues 1 to 388 of SQSTM1; SQSTM1-N397: residues 1 to 397 of SQSTM1; UBA: ubiquitin association; Ubi: ubiquitin.
    Keywords:  3C protease; SQSTM1; VP1; VP3; cleavage; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1897223
  7. Br J Cancer. 2021 Mar 15.
    Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis.
    Chenran Wang, Michael A Haas, Syn Kok Yeo, Ritama Paul, Fuchun Yang, Subrahmanya Vallabhapurapu, Xiaoyang Qi, David R Plas, Jun-Lin Guan.
      BACKGROUND: Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied.METHODS: Using glioma patient database and human glioma cells, we assessed the mechanisms and function of selective autophagy to sustain mTORC1 hyper-activation in glioma.
    RESULTS: We revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with prognosis of glioma patients. Our results indicated that autophagy-mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibitors in combination with 2-Deoxy-D-glucose (2DG) decreased energy production and survival of glioma cells in vitro. Consistently, inhibition of autophagy or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with hyper-activated mTORC1.
    CONCLUSIONS: This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.
    DOI:  https://doi.org/10.1038/s41416-021-01294-0
  8. Cell Death Differ. 2021 Mar 19.
    PKA compartmentalization links cAMP signaling and autophagy.
    Francesca Grisan, Liliana F Iannucci, Nicoletta C Surdo, Andrea Gerbino, Sofia Zanin, Giulietta Di Benedetto, Tullio Pozzan, Konstantinos Lefkimmiatis.
      Autophagy is a highly regulated degradative process crucial for maintaining cell homeostasis. This important catabolic mechanism can be nonspecific, but usually occurs with fine spatial selectivity (compartmentalization), engaging only specific subcellular sites. While the molecular machines driving autophagy are well understood, the involvement of localized signaling events in this process is not well defined. Among the pathways that regulate autophagy, the cyclic AMP (cAMP)/protein kinase A (PKA) cascade can be compartmentalized in distinct functional units called microdomains. However, while it is well established that, depending on the cell type, cAMP can inhibit or promote autophagy, the role of cAMP/PKA microdomains has not been tested. Here we show not only that the effects on autophagy of the same cAMP elevation differ in different cell types, but that they depend on a highly complex sub-compartmentalization of the signaling cascade. We show in addition that, in HT-29 cells, in which autophagy is modulated by cAMP rising treatments, PKA activity is strictly regulated in space and time by phosphatases, which largely prevent the phosphorylation of soluble substrates, while membrane-bound targets are less sensitive to the action of these enzymes. Interestingly, we also found that the subcellular distribution of PKA type-II regulatory PKA subunits hinders the effect of PKA on autophagy, while displacement of type-I regulatory PKA subunits has no effect. Our data demonstrate that local PKA activity can occur independently of local cAMP concentrations and provide strong evidence for a link between localized PKA signaling events and autophagy.
    DOI:  https://doi.org/10.1038/s41418-021-00761-8
  9. Cell Death Discov. 2021 Mar 15. 7(1): 49
    The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro.
    Shiqi Zhang, Zhengbo Shao, Xinna Liu, Mingying Hou, Fang Cheng, Dawei Lei, Huiping Yuan.
      The glaucoma-associated E50K mutation in optineurin (OPTN) is known to affect autophagy and cause the apoptosis of retinal ganglion cells (RGCs), but the pathogenic mechanism remains unclear. In this study, we investigated whether the OPTN (E50K) mutation caused TDP-43 aggregation by disrupting autophagy in vivo and in vitro. OPTN (E50K) mutant mice were generated and analysed for genotype and phenotype. Adeno-associated virus type 2 vectors containing either GFP only, GFP-tagged wild-type OPTN or GFP-tagged E50K-mutated OPTN were used to transfect R28 cells. Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice. Moreover, overexpression of E50K OPTN induced R28 cell apoptosis. Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro. We found that rapamycin effectively reduced the aggregation of TDP-43 in OPTN (E50K) mice and decreased the protein levels of p62/SQSTM1 and the autophagic marker LC3-II. Moreover, rapamycin increased the RGC number and visual function of E50K mice. In addition, we also observed increased cytoplasmic TDP-43 in the spinal cord and motor dysfunction in 24-month-old OPTN (E50K) mice, indicating that TDP-43 accumulation may be the common pathological mechanism of glaucoma and amyotrophic lateral sclerosis (ALS). In conclusion, the disruption of autophagy by OPTN (E50K) affected the degradation of TDP-43 and may play an important role in OPTN (E50K)-mediated glaucomatous retinal neurodegeneration.
    DOI:  https://doi.org/10.1038/s41420-021-00432-0
  10. Front Oncol. 2021 ;11 626309
    Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies.
    Malina Xiao, Alice Benoit, Meriem Hasmim, Caroline Duhem, Guillaume Vogin, Guy Berchem, Muhammad Zaeem Noman, Bassam Janji.
      Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.
    Keywords:  autophagy; cancer resistance; chemotherapy; immunotherapy; radiotherapy; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2021.626309
This page is being maintained by Thomas Krichel. It was last updated on 2023‒05‒08 at 15:41:21.