bims-apauto 2021-06-06 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2021‒06‒06
eleven papers selected by
Su Hyun Lee
Seoul National University

To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death.
TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity.
Autophagy Modulators in Cancer Therapy.
Autophagy and ALS: mechanistic insights and therapeutic implications.
UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation.
Model-based analysis uncovers mutations altering autophagy selectivity in human cancer.
The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51.
Choline kinase alpha 2 acts as a protein kinase to promote lipolysis of lipid droplets.
The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy.
Mitochondrial Autophagy and Cell Survival is Regulated by the Circadian Clock Gene in Cardiac Myocytes during Ischemic Stress.
Selective autophagy as the basis of autophagy-based degraders.

Cells. 2021 May 18. pii: 1235. [Epub ahead of print]10(5):

To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death.

Meenakshi Basu-Shrivastava, Alina Kozoriz, Solange Desagher, Iréna Lassot.

  TRIM17 is a member of the TRIM family, a large class of RING-containing E3 ubiquitin-ligases. It is expressed at low levels in adult tissues, except in testis and in some brain regions. However, it can be highly induced in stress conditions which makes it a putative stress sensor required for the triggering of key cellular responses. As most TRIM members, TRIM17 can act as an E3 ubiquitin-ligase and promote the degradation by the proteasome of substrates such as the antiapoptotic protein MCL1. Intriguingly, TRIM17 can also prevent the ubiquitination of other proteins and stabilize them, by binding to other TRIM proteins and inhibiting their E3 ubiquitin-ligase activity. This duality of action confers several pivotal roles to TRIM17 in crucial cellular processes such as apoptosis, autophagy or cell division, but also in pathological conditions as diverse as Parkinson's disease or cancer. Here, in addition to recent data that endorse this duality, we review what is currently known from public databases and the literature about TRIM17 gene regulation and expression, TRIM17 protein structure and interactions, as well as its involvement in cell physiology and human disorders.

Keywords:  Parkinson’s disease; TRIM17; apoptosis; autism; autophagy; cancer; mitosis; proteolysis; ubiquitination

DOI:  https://doi.org/10.3390/cells10051235
Cell. 2021 May 25. pii: S0092-8674(21)00582-1. [Epub ahead of print]

TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity.

Wenchun Fan, Katrina B Mar, Levent Sari, Ilona K Gaszek, Qiang Cheng, Bret M Evers, John M Shelton, Mary Wight-Carter, Daniel J Siegwart, Milo M Lin, John W Schoggins.

  To control viral infection, vertebrates rely on both inducible interferon responses and less well-characterized cell-intrinsic responses composed of "at the ready" antiviral effector proteins. Here, we show that E3 ubiquitin ligase TRIM7 is a cell-intrinsic antiviral effector that restricts multiple human enteroviruses by targeting viral 2BC, a membrane remodeling protein, for ubiquitination and proteasome-dependent degradation. Selective pressure exerted by TRIM7 results in emergence of a TRIM7-resistant coxsackievirus with a single point mutation in the viral 2C ATPase/helicase. In cultured cells, the mutation helps the virus evade TRIM7 but impairs optimal viral replication, and this correlates with a hyperactive and structurally plastic 2C ATPase. Unexpectedly, the TRIM7-resistant virus has a replication advantage in mice and causes lethal pancreatitis. These findings reveal a unique mechanism for targeting enterovirus replication and provide molecular insight into the benefits and trade-offs of viral evolution imposed by a host restriction factor.

Keywords:  Antiviral immunity; E3 ubiquitin ligase; Enterovirus; Restriction factor; Viral evolution; Viral pathogenesis

DOI:  https://doi.org/10.1016/j.cell.2021.04.047
Int J Mol Sci. 2021 May 28. pii: 5804. [Epub ahead of print]22(11):

Autophagy Modulators in Cancer Therapy.

Kamila Buzun, Agnieszka Gornowicz, Roman Lesyk, Krzysztof Bielawski, Anna Bielawska.

  Autophagy is a process of self-degradation that plays an important role in removing damaged proteins, organelles or cellular fragments from the cell. Under stressful conditions such as hypoxia, nutrient deficiency or chemotherapy, this process can also become the strategy for cell survival. Autophagy can be nonselective or selective in removing specific organelles, ribosomes, and protein aggregates, although the complete mechanisms that regulate aspects of selective autophagy are not fully understood. This review summarizes the most recent research into understanding the different types and mechanisms of autophagy. The relationship between apoptosis and autophagy on the level of molecular regulation of the expression of selected proteins such as p53, Bcl-2/Beclin 1, p62, Atg proteins, and caspases was discussed. Intensive studies have revealed a whole range of novel compounds with an anticancer activity that inhibit or activate regulatory pathways involved in autophagy. We focused on the presentation of compounds strongly affecting the autophagy process, with particular emphasis on those that are undergoing clinical and preclinical cancer research. Moreover, the target points, adverse effects and therapeutic schemes of autophagy inhibitors and activators are presented.

Keywords:  autophagy; autophagy activators; autophagy inhibitors; cancer; cancer therapy

DOI:  https://doi.org/10.3390/ijms22115804
Autophagy. 2021 May 31. 1-29

Autophagy and ALS: mechanistic insights and therapeutic implications.

Jason P Chua, Hortense De Calbiac, Edor Kabashi, Sami J Barmada.

  Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration. This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to refine therapeutic strategies for ALS and related neurodegenerative diseases.Abbreviations: ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CHMP2B: charged multivesicular body protein 2B; DPR: dipeptide repeat; FTD: frontotemporal dementia; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PINK1: PTEN induced kinase 1; RNP: ribonuclear protein; sALS: sporadic ALS; SPHK1: sphingosine kinase 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK-binding kinase 1; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; VCP: valosin containing protein.

Keywords:  Amyotrophic lateral sclerosis; C9orf72; CHMP2B; SQSTM1/p62; TBK1; macroautophagy; mitophagy; myelinophagy; neuronal autophagy; optineurin

DOI:  https://doi.org/10.1080/15548627.2021.1926656
Nat Commun. 2021 06 02. 12(1): 3291

UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation.

Manivannan Subramanian, Seung Jae Hyeon, Tanuza Das, Yoon Seok Suh, Yun Kyung Kim, Jeong-Soo Lee, Eun Joo Song, Hoon Ryu, Kweon Yu.

The formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer's disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD.

DOI: https://doi.org/10.1038/s41467-021-23597-9
Nat Commun. 2021 05 31. 12(1): 3258

Model-based analysis uncovers mutations altering autophagy selectivity in human cancer.

Zhu Han, Weizhi Zhang, Wanshan Ning, Chenwei Wang, Wankun Deng, Zhidan Li, Zehua Shang, Xiaofei Shen, Xiaohui Liu, Otto Baba, Tsuyoshi Morita, Lu Chen, Yu Xue, Da Jia.

Autophagy can selectively target protein aggregates, pathogens, and dysfunctional organelles for the lysosomal degradation. Aberrant regulation of autophagy promotes tumorigenesis, while it is far less clear whether and how tumor-specific alterations result in autophagic aberrance. To form a link between aberrant autophagy selectivity and human cancer, we establish a computational pipeline and prioritize 222 potential LIR (LC3-interacting region) motif-associated mutations (LAMs) in 148 proteins. We validate LAMs in multiple proteins including ATG4B, STBD1, EHMT2 and BRAF that impair their interactions with LC3 and autophagy activities. Using a combination of transcriptomic, metabolomic and additional experimental assays, we show that STBD1, a poorly-characterized protein, inhibits tumor growth via modulating glycogen autophagy, while a patient-derived W203C mutation on LIR abolishes its cancer inhibitory function. This work suggests that altered autophagy selectivity is a frequently-used mechanism by cancer cells to survive during various stresses, and provides a framework to discover additional autophagy-related pathways that influence carcinogenesis.

DOI: https://doi.org/10.1038/s41467-021-23539-5
PLoS Biol. 2021 Jun 02. 19(6): e3001281

The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51.

Jung Mi Park, Seung Wook Yang, Wei Zhuang, Asim K Bera, Yan Liu, Deepak Gurbani, Sergei J von Hoyningen-Huene, Sadie Miki Sakurada, Haiyun Gan, Shondra M Pruett-Miller, Kenneth D Westover, Malia B Potts.

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

DOI: https://doi.org/10.1371/journal.pbio.3001281
Mol Cell. 2021 May 25. pii: S1097-2765(21)00362-2. [Epub ahead of print]

Choline kinase alpha 2 acts as a protein kinase to promote lipolysis of lipid droplets.

Rui Liu, Jong-Ho Lee, Jingyi Li, Rilei Yu, Lin Tan, Yan Xia, Yanhua Zheng, Xue-Li Bian, Philip L Lorenzi, Qianming Chen, Zhimin Lu.

  Lipid droplets are important for cancer cell growth and survival. However, the mechanism underlying the initiation of lipid droplet lipolysis is not well understood. We demonstrate here that glucose deprivation induces the binding of choline kinase (CHK) α2 to lipid droplets, which is sequentially mediated by AMPK-dependent CHKα2 S279 phosphorylation and KAT5-dependent CHKα2 K247 acetylation. Importantly, CHKα2 with altered catalytic domain conformation functions as a protein kinase and phosphorylates PLIN2 at Y232 and PLIN3 at Y251. The phosphorylated PLIN2/3 dissociate from lipid droplets and are degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation, and brain tumor growth. In addition, levels of CHKα2 S279 phosphorylation, CHKα2 K247 acetylation, and PLIN2/3 phosphorylation are positively correlated with one another in human glioblastoma specimens and are associated with poor prognosis in glioblastoma patients. These findings underscore the role of CHKα2 as a protein kinase in lipolysis and glioblastoma development.

Keywords:  AMPK; KAT5; PLIN2/3; acetylation; autophagy; choline kinase; lipid droplet; lipolysis; phosphorylation; tumorigenesis

DOI:  https://doi.org/10.1016/j.molcel.2021.05.005
Cancers (Basel). 2021 May 19. pii: 2475. [Epub ahead of print]13(10):

The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy.

Megan Sheridan, Besim Ogretmen.

  Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid's specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy.

Keywords:  apoptosis; cancer; ceramide; mitophagy; sphingolipids

DOI:  https://doi.org/10.3390/cancers13102475
Autophagy. 2021 Jun 04.

Mitochondrial Autophagy and Cell Survival is Regulated by the Circadian Clock Gene in Cardiac Myocytes during Ischemic Stress.

Inna Rabinovich-Nikitin, Mina Rasouli, Cristine J Reitz, Illana Posen, Victoria Margulets, Rimpy Dhingra, Tarak N Khatua, James A Thliveris, Tami A Martino, Lorrie A Kirshenbaum.

  Cardiac function is highly reliant on mitochondrial oxidative metabolism and quality control. The circadian Clock gene is critically linked to vital physiological processes including mitochondrial fission, fusion and bioenergetics; however, little is known of how the Clock gene regulates these vital processes in the heart. Herein, we identified a putative circadian CLOCK-mitochondrial interactome that gates an adaptive survival response during myocardial ischemia. We show by transcriptome and gene ontology mapping in CLOCK Δ19/Δ19 mouse that Clock transcriptionally coordinates the efficient removal of damaged mitochondria during myocardial ischemia by directly controlling transcription of genes required for mitochondrial fission, fusion and macroautophagy/autophagy. Loss of Clock gene activity impaired mitochondrial turnover resulting in the accumulation of damaged reactive oxygen species (ROS)-producing mitochondria from impaired mitophagy. This coincided with ultrastructural defects to mitochondria and impaired cardiac function. Interestingly, wild type CLOCK but not mutations of CLOCK defective for E-Box binding or interaction with its cognate partner ARNTL/BMAL-1 suppressed mitochondrial damage and cell death during acute hypoxia. Interestingly, the autophagy defect and accumulation of damaged mitochondria in CLOCK-deficient cardiac myocytes were abrogated by restoring autophagy/mitophagy. Inhibition of autophagy by ATG7 knockdown abrogated the cytoprotective effects of CLOCK. Collectively, our results demonstrate that CLOCK regulates an adaptive stress response critical for cell survival by transcriptionally coordinating mitochondrial quality control mechanisms in cardiac myocytes. Interdictions that restore CLOCK activity may prove beneficial in reducing cardiac injury in individuals with disrupted circadian CLOCK.

Keywords:  autophagy; clock; metabolism; mitochondrion; myocardial infarction

DOI:  https://doi.org/10.1080/15548627.2021.1938913
Cell Chem Biol. 2021 May 22. pii: S2451-9456(21)00223-3. [Epub ahead of print]

Selective autophagy as the basis of autophagy-based degraders.

Daiki Takahashi, Hirokazu Arimoto.

  Degrader technologies, which enable the chemical knockdown of disease-causing proteins, are promising for drug discovery. After two decades of research, degraders using the ubiquitin-proteasome system (UPS) are currently in clinical trials. However, the UPS substrates are mainly limited to soluble proteins. Autophagy-targeting chimeras and autophagosome-tethering compounds are degraders that use autophagy, which has functions complementary to the UPS. They can degrade organelles and aggregate-prone proteins, making them promising treatments against age-related conditions such as mitochondrial dysfunction and neurodegenerative diseases. The molecular mechanism of selective autophagy is an ongoing research topic, which explains why autophagy-based degraders were not available until recently. In this review, we introduce four classifications of selective autophagy mechanisms to facilitate the understanding of the degrader design.

Keywords:  ATTEC; AUTAC; LLPS; S-guanylation; aggregates; autophagy; degrader; mitochondria; p62; ubiquitin

DOI:  https://doi.org/10.1016/j.chembiol.2021.05.006