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Publication : MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER-mitochondria contact sites.

First Author  Takeda K Year  2019
Journal  EMBO J Volume  38
Issue  15 Pages  e100999
PubMed ID  31368599 Mgi Jnum  J:282242
Mgi Id  MGI:6369894 Doi  10.15252/embj.2018100999
Citation  Takeda K, et al. (2019) MITOL prevents ER stress-induced apoptosis by IRE1alpha ubiquitylation at ER-mitochondria contact sites. EMBO J 38(15):e100999
abstractText  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/MARCH5) inhibits ER stress-induced apoptosis through ubiquitylation of IRE1alpha at the mitochondria-associated ER membrane (MAM). MITOL promotes K63-linked chain ubiquitination of IRE1alpha at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1alpha and regulated IRE1alpha-dependent decay (RIDD). Therefore, under ER stress, MITOL depletion or the IRE1alpha mutant (K481R) allows for IRE1alpha 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 IRE1alpha ubiquitylation, suggesting that this directs the apoptotic switch of IRE1alpha signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE1alpha ubiquitylation by MITOL at the MAM.
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