Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation
Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation
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DOI：
10.1016/j.bbrc.2022.04.007
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发表时间：
2022-04-09
影响因子：
3.1
通讯作者：
Kobayashi, Hatasu
中科院分区：
文献类型：
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作者：
Ahmed, Sharif;Habu, Toshiyuki;Kobayashi, Hatasu
RNF 213是烟雾病的易感基因，与对各种应激源的应激反应有关。我们先前报道了Rnf 213基因敲除（KO）减轻了糖尿病秋田小鼠模型中内质网（ER）应激诱导的糖尿病。然而，RNF 213在ER应激调节中的作用仍然未知。在本研究中，RNF 213敲低显著抑制HeLa细胞中化学ER应激诱导剂对ER应激标志物（CHOP和剪接的XBP 1）的上调。SEL 1 L是ER相关降解（ERAD）中的关键分子，其水平通过RNF 213敲低而增加，并且SEL 1 L敲低阻止了RNF 213抑制对HeLa细胞中ER应激的抑制作用，表明SEL 1 L参与了这种ER应激的抑制。在Rnf 213 KO/秋田小鼠的胰岛和Rnf 213 KO小鼠胚胎成纤维细胞中也证实了SEL 1 L上调。此外，RNF 213抑制增加了HRD 1的水平，HRD 1与SEL 1 L形成复合物，以降解ER应激下细胞中的错误折叠蛋白。总之，我们证明RNF 213耗竭可能通过升高SEL 1 L-HRD 1复合物来抑制ER应激，从而促进体外和体内ERAD。(c)2022年由Elsevier Inc.出版
RNF213, a susceptibility gene for moyamoya disease, is associated with stress responses to various stressors. We previously reported that Rnf213 knockout (KO) mitigated endoplasmic reticulum (ER) stress-induced diabetes in the Akita mouse model of diabetes. However, the role of RNF213 in ER stress regulation remains unknown. In the present study, RNF213 knockdown significantly inhibited the upregulation of ER stress markers (CHOP and spliced XBP1) by chemical ER stress-inducers in HeLa cells. Levels of SEL1L, a critical molecule in ER-associated degradation (ERAD), were increased by RNF213 knockdown, and SEL1L knockdown prevented the inhibitory effect of RNF213 suppression on ER stress in HeLa cells, indicating SEL1L involvement in this inhibition of ER stress. SEL1L upregulation was also confirmed in pancreatic islets of Rnf213 KO/Akita mice and in Rnf213 KO mouse embryonic fibroblasts. Additionally, RNF213 suppression increased levels of HRD1, which forms a complex with SEL1L to degrade misfolded protein in cells under ER stress. In conclusion, we demonstrate that RNF213 depletion inhibits ER stress possibly through elevation of the SEL1L-HRD1 complex, thereby promoting ERAD in vitro and in vivo.(c) 2022 Published by Elsevier Inc.