MITOL prevents ER stress-induced apoptosis via IRE1α ubiquitylation at ER-mitochondria contact sites Keisuke Takeda and Shigeru Yanagi, Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences
We have previously identified mitochondrial ubiquitin ligase (MITOL/MARCH5) and demonstrated that MITOL ubiquitinates mitofusin 2 (Mfn2) and enhances its GTPase activity, resulting in the tethering between the endoplasmic reticulum (ER) and mitochondria (1, 2). Interestingly, silencing of MITOL expression reduced the integrity of ER network and caused vulnerability to ER stress, suggesting a regulatory role of MITOL in ER stress response. On the other hand, unresolved ER stress shifts the unfolded protein response signalling from cell survival to cell death, although the switching mechanism remains unclear. Here, we report that MITOL inhibits ER stress-induced apoptosis via IRE1α ubiquitylation at the mitochondria-associated ER membrane (MAM). MITOL adds lysine (K) 63-linked polyubiquitin chain to K481 of IRE1α, thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay of mRNA (RIDD) activity. Therefore, under ER stress, MITOL depletion or overexpression of IRE1α mutant (K481R) allows IRE1α hyper-oligomerization and enhances RIDD activity, resulting in apoptosis. Similarly, in the MITOL-deficient mouse spinal cord, ER stress enhances RIDD activity and subsequent apoptosis. Notably, unresolved ER stress attenuates IRE1α ubiquitylation, suggesting this directs apoptotic switch of IRE1α signalling. Our findings provide a novel concept that mitochondria determine cell fate under ER stress through IRE1α regulation by MITOL at the MAM.
References 1. Yonashiro et al., EMBO J. 2006 2. Sugiura et al., Mol. Cell 2013
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