bims-apauto 2022-01-09 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2022‒01‒09
eight papers selected by
Su Hyun Lee
Seoul National University

Restoration of mitophagy ameliorates cardiomyopathy in Barth syndrome.
Identification of an autoinhibitory, mitophagy-inducing peptide derived from the transmembrane domain of USP30.
LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.
Autophagy in cancer: The cornerstone during glutamine deprivation.
Presynaptic Autophagy and the Connection With Neurotransmission.
SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer.
L-asparaginase mediated therapy in L-asparagine auxotrophic cancers: A review.
SARS-CoV-2 NSP13 Inhibits Type I IFN Production by Degradation of TBK1 via p62-Dependent Selective Autophagy.

Autophagy. 2022 Jan 05. 1-16

Restoration of mitophagy ameliorates cardiomyopathy in Barth syndrome.

Jun Zhang, Xueling Liu, Jia Nie, Yuguang Shi.

  Barth syndrome (BTHS) is an X-linked genetic disorder caused by mutations in the TAFAZZIN/Taz gene which encodes a transacylase required for cardiolipin remodeling. Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining mitochondrial membrane structure, respiration, mtDNA biogenesis, and mitophagy. Mutations in the TAFAZZIN gene deplete mature cardiolipin, leading to mitochondrial dysfunction, dilated cardiomyopathy, and premature death in BTHS patients. Currently, there is no effective treatment for this debilitating condition. In this study, we showed that TAFAZZIN deficiency caused hyperactivation of MTORC1 signaling and defective mitophagy, leading to accumulation of autophagic vacuoles and dysfunctional mitochondria in the heart of Tafazzin knockdown mice, a rodent model of BTHS. Consequently, treatment of TAFAZZIN knockdown mice with rapamycin, a potent inhibitor of MTORC1, not only restored mitophagy, but also mitigated mitochondrial dysfunction and dilated cardiomyopathy. Taken together, these findings identify MTORC1 as a novel therapeutic target for BTHS, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for BTHS.Abbreviations: BTHS: Barth syndrome; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CL: cardiolipin; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; KD: knockdown; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LV: left ventricle; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; OCR: oxygen consumption rate; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; qRT-PCR: quantitative real-time polymerase chain reaction; RPS6KB/S6K: ribosomal protein S6 kinase beta; SQSTM1/p62: sequestosome 1; TLCL: tetralinoleoyl cardiolipin; WT: wild-type.

Keywords:  BTHS; MTORC1; TAFAZZIN; cardiolipin; mitophagy; rapamycin

DOI:  https://doi.org/10.1080/15548627.2021.2020979
Autophagy. 2022 Jan 06. 1-20

Identification of an autoinhibitory, mitophagy-inducing peptide derived from the transmembrane domain of USP30.

Xuan Qin, Rui Wang, Hongkun Xu, Licheng Tu, Hailing Chen, Heng Li, Na Liu, Jinpeng Wang, Shuiming Li, Feng Yin, Naihan Xu, Zigang Li.

  The mitochondrial-anchored deubiquitinating enzyme USP30 (ubiquitin specific peptidase 30) antagonizes PRKN/parkin-mediated mitophagy, making it a potential target for treating Parkinson disease. However, few inhibitors targeting USP30 have been reported. Here, we report a novel peptide (Q14) derived from the transmembrane (TM) domain of USP30 that can target mitochondrial-anchored USP30 directly and increase mitophagy through two intriguing and distinct mechanisms: a novel autoinhibition mechanism in USP30 and accelerated autophagosome formation via the LC3-interacting region (LIR) of the Q14 peptide. We identified the potential binding sites between the Q14 peptide and USP30 and postulated that an allosteric autoinhibition mechanism regulates USP30 activity. Furthermore, the LIR motif in the Q14 peptide offers additional binding with LC3 and accelerated autophagosome formation. The two mechanisms synergistically enhance mitophagy. Our work provides novel insight and direction to the design of inhibitors for USP30 or other deubiquitinating enzymes (DUBs).Abbreviations: 3-MA: 3-methyladenine; ATTEC: autophagosome-tethering compound; BafA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DMSO: dimethyl sulfoxide; FP: fluorescence polarization; FUNDC1: FUN14 domain containing 1; HCQ: hydroxychloroquine; LIR: LC3-interacting region; MST: microscale thermophoresis; mtDNA: mitochondrial DNA; mtPA-GFP: mitochondria-targeted photoactive fluorescence protein; OMM: outer mitochondrial membrane; PINK1: PTEN induced kinase 1; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; Rap: rapamycin; SA: streptavidin; TM: transmembrane; Ub: ubiquitin; Ub-AMC: Ub-7-amido-4-methylcoumarin; UPS: ubiquitin-protease system; USP: ubiquitin specific peptidase; USP30: ubiquitin specific peptidase 30.

Keywords:  Autoinhibition; USP30; mitophagy; peptide inhibitor; transmembrane

DOI:  https://doi.org/10.1080/15548627.2021.2022360
J Clin Invest. 2022 Jan 06. pii: e153157. [Epub ahead of print]

LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.

Jamie A Moore, Jayna J Mistry, Charlotte Hellmich, Rebecca H Horton, Edyta E Wojtowicz, Aisha Jibril, Matthew Jefferson, Thomas Wileman, Naiara Beraza, Kristian M Bowles, Stuart A Rushworth.

  The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to, and growth of, solid tumors. Here we investigated the role of macrophage LC3-associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages increased AML growth in-vivo. We showed that LAP is the predominate method of BM macrophage phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to accumulation of apoptotic cells (AC) and apoptotic bodies (AB) resulting in accelerated leukemia growth. Mechanistically, LAP of AMLderived-AB by BM macrophages, resulted in STING pathway activation. We identified that AML derived mitochondrial damage associated molecular patterns were processed by BM macrophages via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML derived-AB showed that it is this mtDNA which was responsible for the induction of STING signalling in BM macrophages. Phenotypically we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.

Keywords:  Autophagy; Hematology; Leukemias; Mitochondria; Oncology

DOI:  https://doi.org/10.1172/JCI153157
Eur J Pharmacol. 2021 Dec 30. pii: S0014-2999(21)00879-7. [Epub ahead of print] 174723

Autophagy in cancer: The cornerstone during glutamine deprivation.

Hamza M Fares, Xiaodan Lyu, Xiaoting Xu, Renchao Dong, Muyao Ding, Shichao Mi, Yifan Wang, Xue Li, Shengtao Yuan, Li Sun.

  Over the past two decades, researchers have revealed the crucial functions of glutamine in supporting the hyperproliferation state of cancer cells. Glutamine acts on maintaining high energy production, supporting redox status and amino acid homeostasis. Therefore, cancer cells exhibit excessive uptake of the extracellular glutamine, synthesize it in some cases, and recycle intracellular and extracellular proteins to provide an additional source of glutamine to satisfy the increasing glutamine demand. On the other hand, autophagy's role is still debated regarding tumor initiation and progression. However, most cancer cells urgently need autophagy to overcome the existential threats during glutamine restriction stress. Downstream to various stress pathways induced during such a condition, autophagy is considered an indispensable cytoprotective tool to maintain cell integrity and survival. However, the overactivation of the autophagy process is related to lethal consequences. This review summarized glutamine pathways to control autophagy and highlighted autophagy's primary activation pathways, and discussed the roles during glutamine deprivation.

Keywords:  Autophagy; Cancer cell metabolism; Glutamine deprivation

DOI:  https://doi.org/10.1016/j.ejphar.2021.174723
Front Cell Dev Biol. 2021 ;9 790721

Presynaptic Autophagy and the Connection With Neurotransmission.

Marianna Decet, Patrik Verstreken.

  Autophagy is an evolutionary conserved catabolic pathway essential for the maintenance of cellular homeostasis. Defective proteins and organelles are engulfed by autophagosomal membranes which fuse with lysosomes for cargo degradation. In neurons, the orchestrated progression of autophagosome formation and maturation occurs in distinct subcellular compartments. For synapses, the distance from the soma and the oxidative stress generated during intense neuronal activity pose a challenge to maintain protein homeostasis. Autophagy constitutes a crucial mechanism for proper functioning of this unique and vulnerable cellular compartment. We are now beginning to understand how autophagy is regulated at pre-synaptic terminals and how this pathway, when imbalanced, impacts on synaptic function and -ultimately- neuronal survival. We review here the current state of the art of "synaptic autophagy", with an emphasis on the biogenesis of autophagosomes at the pre-synaptic compartment. We provide an overview of the existing knowledge on the signals inducing autophagy at synapses, highlight the interplay between autophagy and neurotransmission, and provide perspectives for future research.

Keywords:  macroautophagy; neurotransmission; synapse; synaptic autophagy; vesicle cycling

DOI:  https://doi.org/10.3389/fcell.2021.790721
Cell Death Differ. 2022 Jan 06.

SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer.

Qing Shi, Xiaofeng Jin, Pingzhao Zhang, Qian Li, Zeheng Lv, Yan Ding, Huiying He, Yijun Wang, Yuanlong He, Xiaying Zhao, Shi-Min Zhao, Yao Li, Kun Gao, Chenji Wang.

p62/SQSTM1 is a selective autophagy receptor that drives ubiquitinated cargos towards autophagic degradation. This receptor is also a stress-induced scaffold protein that helps cells to cope with oxidative stress through activation of the Nrf2 pathway. Functional disorders of p62 are closely associated with multiple neurodegenerative diseases and cancers. The gene encoding the E3 ubiquitin ligase substrate-binding adapter SPOP is frequently mutated in prostate cancer (PCa), but the molecular mechanisms underlying how SPOP mutations contribute to PCa tumorigenesis remain poorly understood. Here, we report that cytoplasmic SPOP binds and induces the non-degradative ubiquitination of p62 at residue K420 within the UBA domain. This protein modification decreases p62 puncta formation, liquid phase condensation, dimerization, and ubiquitin-binding capacity, thereby suppressing p62-dependent autophagy. Moreover, we show that SPOP relieves p62-mediated Keap1 sequestration, which ultimately decreases Nrf2-mediated transcriptional activation of antioxidant genes. We further show that PCa-associated SPOP mutants lose the capacity to ubiquitinate p62 and instead promote autophagy and the redox response in a dominant-negative manner. Thus, our findings indicate oncogenic roles of autophagy and Nrf2 activation in the tumorigenesis of SPOP-mutated PCa.

DOI: https://doi.org/10.1038/s41418-021-00913-w
Anticancer Agents Med Chem. 2022 Jan 06.

L-asparaginase mediated therapy in L-asparagine auxotrophic cancers: A review.

Sindhu R, H K Manonmani.

  Microbial L-asparaginase is the most effective first-line therapeutic used in the treatment protocols of paediatric and adult leukemia. Leukemic cell's auxotrophy for L-asparagine is exploited as a therapeutic strategy to mediate cell death through metabolic blockade of L-asparagine using L-asparaginase. Escherichia coli and Erwinia chrysanthemi serve as the major enzyme deriving sources accepted in clinical practise and the enzyme has bestowed improvements in patient outcomes over the last 40 years. However, an array of side effects generated by the native enzymes due to glutamine co-catalysis and short serum stays augmenting frequent dosages, intended a therapeutic switch towards the development of biobetter alternatives for the enzyme including the formulations resulting in sustained local depletion of L-asparagine. In addition, the treatment with L-asparaginase in few cancer types has proven to elicit drug-induced cytoprotective autophagy mechanisms and therefore warrants concern. Although the off-target glutamine hydrolysis has been viewed in contributing the drug-induced secondary responses in cells deficient with asparagine synthetase machinery, the beneficial role of glutaminase-asparaginase in proliferative regulation of asparagine prototrophic cells has been looked forward. The current review provides an overview on the enzyme's clinical applications in leukemia and possible therapeutic implications in other solid tumours, recent advancements in drug formulations, and discusses the aspects of two-sided roles of glutaminase-asparaginases and drug-induced cytoprotective autophagy mechanisms.

Keywords:  L-asparaginase; acute lymphoblastic leukemia; autophagy; biobetters; glutaminase-asparaginase; solid tumours

DOI:  https://doi.org/10.2174/1871520622666220106103336
J Immunol. 2022 Jan 07. pii: ji2100684. [Epub ahead of print]

SARS-CoV-2 NSP13 Inhibits Type I IFN Production by Degradation of TBK1 via p62-Dependent Selective Autophagy.

Chao Sui, Tongyang Xiao, Shengyuan Zhang, Hongxiang Zeng, Yi Zheng, Bingyu Liu, Gang Xu, Chengjiang Gao, Zheng Zhang.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has seriously threatened global public health. Severe COVID-19 has been reported to be associated with an impaired IFN response. However, the mechanisms of how SARS-CoV-2 antagonizes the host IFN response are poorly understood. In this study, we report that SARS-CoV-2 helicase NSP13 inhibits type I IFN production by directly targeting TANK-binding kinase 1 (TBK1) for degradation. Interestingly, inhibition of autophagy by genetic knockout of Beclin1 or pharmacological inhibition can rescue NSP13-mediated TBK1 degradation in HEK-293T cells. Subsequent studies revealed that NSP13 recruits TBK1 to p62, and the absence of p62 can also inhibit TBK1 degradation in HEK-293T and HeLa cells. Finally, TBK1 and p62 degradation and p62 aggregation were observed during SARS-CoV-2 infection in HeLa-ACE2 and Calu3 cells. Overall, our study shows that NSP13 inhibits type I IFN production by recruiting TBK1 to p62 for autophagic degradation, enabling it to evade the host innate immune response, which provides new insights into the transmission and pathogenesis of SARS-CoV-2 infection.

DOI: https://doi.org/10.4049/jimmunol.2100684