MITOL prevents ER stress-induced apoptosis by IRE1? ubiquitylation at ER-mitochondria contact sites.

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 IRE1? at the mitochondria-associated ER membrane (MAM). MITOL promotes K63-linked chain ubiquitination ...
of IRE1? at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1? and regulated IRE1?-dependent decay (RIDD). Therefore, under ER stress, MITOL depletion or the IRE1? mutant (K481R) allows for IRE1? 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 IRE1? ubiquitylation, suggesting that this directs the apoptotic switch of IRE1? signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE1? ubiquitylation by MITOL at the MAM.
Mesh Terms:
Animals, Apoptosis, COS Cells, Cell Line, Chlorocebus aethiops, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Endoribonucleases, HEK293 Cells, HeLa Cells, Humans, Lysine, Membrane Proteins, Mice, Mitochondria, Protein-Serine-Threonine Kinases, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination
EMBO J.
Date: Dec. 01, 2018
Download Curated Data For This Publication
222435
Switch View:
  • Interactions 8