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

Keisuke Takeda, Shun Nagashima, Isshin Shiiba, Aoi Uda, Takeshi Tokuyama, Naoki Ito, Toshifumi Fukuda, Nobuko Matsushita, Satoshi Ishido, Takao Iwawaki, Takashi Uehara, Ryoko Inatome, Shigeru Yanagi

Research output: Contribution to journal › Article

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.

Original languageEnglish
Article numbere100999
JournalEMBO Journal
DOIs
Publication statusPublished - Jan 1 2019

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Endoplasmic Reticulum Stress
Ubiquitination
Apoptosis
Mitochondria
Oligomerization
Membranes
Unfolded Protein Response
Cell death
Ligases
Ubiquitin
Endoplasmic Reticulum
Lysine
Cell Survival
Spinal Cord
Cell Death
Cells
Switches
Proteins

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Takeda, K., Nagashima, S., Shiiba, I., Uda, A., Tokuyama, T., Ito, N., ... Yanagi, S. (2019). MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER–mitochondria contact sites. EMBO Journal, [e100999]. https://doi.org/10.15252/embj.2018100999

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

In: EMBO Journal, 01.01.2019.

Research output: Contribution to journal › Article

Takeda, K, Nagashima, S, Shiiba, I, Uda, A, Tokuyama, T, Ito, N, Fukuda, T, Matsushita, N, Ishido, S, Iwawaki, T, Uehara, T, Inatome, R & Yanagi, S 2019, 'MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER–mitochondria contact sites', EMBO Journal. https://doi.org/10.15252/embj.2018100999
Takeda K, Nagashima S, Shiiba I, Uda A, Tokuyama T, Ito N et al. MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER–mitochondria contact sites. EMBO Journal. 2019 Jan 1. e100999. https://doi.org/10.15252/embj.2018100999
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. / MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER–mitochondria contact sites. In: EMBO Journal. 2019.
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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.",
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AU - Tokuyama, Takeshi

AU - Ito, Naoki

AU - Fukuda, Toshifumi

AU - Matsushita, Nobuko

AU - Ishido, Satoshi

AU - Iwawaki, Takao

AU - Uehara, Takashi

AU - Inatome, Ryoko

AU - Yanagi, Shigeru

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