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

Content Provider	Europe PMC
Author	Jeon, Seo Jeong Chung, Kwang Chul
Copyright Year	2022
Abstract	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.
ISSN	00219258
Volume Number	298
PubMed Central reference number	PMC9547223
Issue Number	10
PubMed reference number	36075291
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2022.102464
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2022-09-06
Access Restriction	Open
Rights License	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). © 2022 The Authors
Subject Keyword	AIF ubiquitin-like ISG15 HERC5 etoposide apoptosis A549 AIF, apoptosis-inducing factor co-IP, coimmunoprecipitation HA, hemagglutinin HEK293, human embryonic kidney 293 LDH, lactate dehydrogenase MNNG, N-methyl-N-nitro-N′-nitrosoguanidine PI, propidium iodide PLA, proximity ligation assay PTM, posttranslational modification tAIF, truncated AIF
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry