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 language | English |
|---|---|
| Article number | e100999 |
| Journal | EMBO Journal |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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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
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
}
TY - JOUR
T1 - MITOL prevents ER stress-induced apoptosis by IRE1α ubiquitylation at ER–mitochondria contact sites
AU - Takeda, Keisuke
AU - Nagashima, Shun
AU - Shiiba, Isshin
AU - Uda, Aoi
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
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - apoptosis
KW - IRE1α
KW - mitochondria-associated ER membrane
KW - mitochondrial E3 ligase MITOL/MARCH5
KW - unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=85067410920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067410920&partnerID=8YFLogxK
U2 - 10.15252/embj.2018100999
DO - 10.15252/embj.2018100999
M3 - Article
C2 - 31368599
AN - SCOPUS:85067410920
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
M1 - e100999
ER -