1. Academic Validation
  2. MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER-mitochondria contact sites

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

  • EMBO J. 2019 Aug 1;38(15):e100999. doi: 10.15252/embj.2018100999.
Keisuke Takeda 1 Shun Nagashima 1 Isshin Shiiba 1 Aoi Uda 1 Takeshi Tokuyama 1 Naoki Ito 1 Toshifumi Fukuda 1 Nobuko Matsushita 1 Satoshi Ishido 2 Takao Iwawaki 3 Takashi Uehara 4 Ryoko Inatome 1 Shigeru Yanagi 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
  • 2 Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan.
  • 3 Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan.
  • 4 Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Abstract

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 IRE1α at the mitochondria-associated ER membrane (MAM). MITOL promotes K63-linked chain ubiquitination of IRE1α at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay (RIDD). Therefore, under ER stress, MITOL depletion or the IRE1α mutant (K481R) allows for IRE1α 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 IRE1α ubiquitylation, suggesting that this directs the apoptotic switch of IRE1α signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE1α ubiquitylation by MITOL at the MAM.

Keywords

IRE1α; apoptosis; mitochondria-associated ER membrane; mitochondrial E3 ligase MITOL/MARCH5; unfolded protein response.

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Products
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    Product Name
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  • HY-17537
    99.90%, IRE1抑制剂