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Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death

Apoptosis-inducing factor (AIF) is a mitochondrion-localized flavoprotein with NADH oxidase activity. AIF normally acts as an oxidoreductase to catalyze the transfer of electrons between molecules, but it can also kill cells when exposed to certain stimuli. For example, intact AIF is cleaved upon ex...

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Autores principales: Jeon, Seo Jeong, Chung, Kwang Chul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9547223/
https://www.ncbi.nlm.nih.gov/pubmed/36075291
http://dx.doi.org/10.1016/j.jbc.2022.102464
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author Jeon, Seo Jeong
Chung, Kwang Chul
author_facet Jeon, Seo Jeong
Chung, Kwang Chul
author_sort Jeon, Seo Jeong
collection PubMed
description Apoptosis-inducing factor (AIF) is a mitochondrion-localized flavoprotein with NADH oxidase activity. AIF normally acts as an oxidoreductase to catalyze the transfer of electrons between molecules, but it can also kill cells when exposed to certain stimuli. For example, intact AIF is cleaved upon exposure to DNA-damaging agents such as etoposide, and truncated AIF (tAIF) is released from the mitochondria to the cytoplasm and translocated to the nucleus where it induces apoptosis. Although the serial events during tAIF-mediated apoptosis and the transition of AIF function have been widely studied from various perspectives, their underlying regulatory mechanisms and the factors involved are not fully understood. Here, we demonstrated that tAIF is a target of the covalent conjugation of the ubiquitin-like moiety ISG15 (referred to as ISGylation), which is mediated by the ISG15 E3 ligase HERC5. In addition, ISGylation increases the stability of tAIF protein as well as its K6-linked polyubiquitination. Moreover, we found that ISGylation increases the nuclear translocation of tAIF upon cytotoxic etoposide treatment, subsequently causing apoptotic cell death in human lung A549 carcinoma cells. Collectively, these results suggest that HERC5-mediated ISG15 conjugation is a key factor in the positive regulation of tAIF-mediated apoptosis, highlighting a novel role of posttranslational ISG15 modification as a switch that allows cells to live or die under the stress that triggers tAIF release.
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spelling pubmed-95472232022-10-14 Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death Jeon, Seo Jeong Chung, Kwang Chul J Biol Chem Research Article Apoptosis-inducing factor (AIF) is a mitochondrion-localized flavoprotein with NADH oxidase activity. AIF normally acts as an oxidoreductase to catalyze the transfer of electrons between molecules, but it can also kill cells when exposed to certain stimuli. For example, intact AIF is cleaved upon exposure to DNA-damaging agents such as etoposide, and truncated AIF (tAIF) is released from the mitochondria to the cytoplasm and translocated to the nucleus where it induces apoptosis. Although the serial events during tAIF-mediated apoptosis and the transition of AIF function have been widely studied from various perspectives, their underlying regulatory mechanisms and the factors involved are not fully understood. Here, we demonstrated that tAIF is a target of the covalent conjugation of the ubiquitin-like moiety ISG15 (referred to as ISGylation), which is mediated by the ISG15 E3 ligase HERC5. In addition, ISGylation increases the stability of tAIF protein as well as its K6-linked polyubiquitination. Moreover, we found that ISGylation increases the nuclear translocation of tAIF upon cytotoxic etoposide treatment, subsequently causing apoptotic cell death in human lung A549 carcinoma cells. Collectively, these results suggest that HERC5-mediated ISG15 conjugation is a key factor in the positive regulation of tAIF-mediated apoptosis, highlighting a novel role of posttranslational ISG15 modification as a switch that allows cells to live or die under the stress that triggers tAIF release. American Society for Biochemistry and Molecular Biology 2022-09-06 /pmc/articles/PMC9547223/ /pubmed/36075291 http://dx.doi.org/10.1016/j.jbc.2022.102464 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Jeon, Seo Jeong
Chung, Kwang Chul
Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death
title Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death
title_full Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death
title_fullStr Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death
title_full_unstemmed Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death
title_short Covalent conjugation of ubiquitin-like ISG15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death
title_sort covalent conjugation of ubiquitin-like isg15 to apoptosis-inducing factor exacerbates toxic stimuli-induced apoptotic cell death
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9547223/
https://www.ncbi.nlm.nih.gov/pubmed/36075291
http://dx.doi.org/10.1016/j.jbc.2022.102464
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AT chungkwangchul covalentconjugationofubiquitinlikeisg15toapoptosisinducingfactorexacerbatestoxicstimuliinducedapoptoticcelldeath