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MITOL prevents ER stress‐induced apoptosis by IRE 1α ubiquitylation at ER –mitochondria contact sites
Author(s) -
Takeda Keisuke,
Nagashima Shun,
Shiiba Isshin,
Uda Aoi,
Tokuyama Takeshi,
Ito Naoki,
Fukuda Toshifumi,
Matsushita Nobuko,
Ishido Satoshi,
Iwawaki Takao,
Uehara Takashi,
Inatome Ryoko,
Yanagi Shigeru
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100999
Subject(s) - pharmacy , biological sciences , chemistry , library science , medicine , biology , microbiology and biotechnology , family medicine , computer science
Unresolved endoplasmic reticulum ( ER ) stress shifts the unfolded protein response signaling from cell survival to cell death, although the switching mechanism remains unclear. Here, we report that mitochondrial ubiquitin ligase ( MITOL / MARCH 5) inhibits ER stress‐induced apoptosis through ubiquitylation of IRE 1α at the mitochondria‐associated ER membrane ( MAM ). MITOL promotes K63‐linked chain ubiquitination of IRE 1α at lysine 481 (K481), thereby preventing hyper‐oligomerization of IRE 1α and regulated IRE 1α‐dependent decay ( RIDD ). Therefore, under ER stress, MITOL depletion or the IRE 1α mutant (K481R) allows for IRE 1α hyper‐oligomerization and enhances RIDD activity, resulting in apoptosis. Similarly, in the spinal cord of MITOL ‐deficient mice, ER stress enhances RIDD activity and subsequent apoptosis. Notably, unresolved ER stress attenuates IRE 1α ubiquitylation, suggesting that this directs the apoptotic switch of IRE 1α signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE 1α ubiquitylation by MITOL at the MAM .