Endoplasmic reticulum associated degradation is required for maintaining endoplasmic reticulum homeostasis and viability of mature Schwann cells in adults.
Endoplasmic reticulum associated degradation is required for maintaining endoplasmic reticulum homeostasis and viability of mature Schwann cells in adults.
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作者：
Wu S;Stone S;Yue Y;Lin W
整合未折叠蛋白应答(UPR)和内质网相关降解(ERAD)是维持内质网(ER)动态平衡的主要机制。雪旺细胞(Schwann cell，SCs)必须通过内质网产生大量的髓鞘蛋白，以组装和维持髓鞘结构；然而，目前尚不清楚SCs如何维持内质网的动态平衡。已知，类LIN-12的抑制/增强子(Sel1L)是Sel1L-羟甲基戊二酰基还原酶降解蛋白1(Hrd1)复合体ERAD活性所必需的。在这里，我们证明了干细胞中Sel1L缺乏会损害Sel1L-Hrd1复合体的ERAD活性，导致内质网应激和UPR的激活。有趣的是，Sel1L缺乏对发育过程中活跃的髓鞘干细胞没有影响，但导致成年PNS中较晚发病的成熟SC凋亡和脱髓鞘。此外，UPR的胰腺ER激酶(PERK)分支失活不会影响主动髓鞘干细胞的活性和功能，但会加剧SC特异性Sel1L缺陷小鼠的内质网应激和成熟SCs的凋亡。这些发现表明，整合的UPR和ERAD对于发育过程中活跃的髓鞘干细胞是必不可少的，但对于维持ER动态平衡以及成年成熟干细胞的生存和功能是必要的。
The integrated unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) is the principle mechanisms that maintain endoplasmic reticulum (ER) homeostasis. Schwann cells (SCs) must produce an enormous amount of myelin proteins via the ER to assemble and maintain myelin structure; however, it is unclear how SCs maintain ER homeostasis. It is known that Suppressor/Enhancer of Lin-12-like (Sel1L) is necessary for the ERAD activity of the Sel1L- hydroxymethylglutaryl reductase degradation protein 1(Hrd1) complex. Herein, we showed that Sel1L deficiency in SCs impaired the ERAD activity of the Sel1L-Hrd1 complex and led to ER stress and activation of the UPR. Interestingly, Sel1L deficiency had no effect on actively myelinating SCs during development, but led to later-onset mature SC apoptosis and demyelination in the adult PNS. Moreover, inactivation of the pancreatic ER kinase (PERK) branch of the UPR did not influence the viability and function of actively myelinating SCs, but resulted in exacerbation of ER stress and apoptosis of mature SCs in SC-specific Sel1L deficient mice. These findings suggest that the integrated UPR and ERAD is dispensable to actively myelinating SCs during development, but is necessary for maintaining ER homeostasis and the viability and function of mature SCs in adults.
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影响因子：
2.9
作者：
Clayton, Benjamin L. L.;Popko, Brian
通讯作者：
Popko, Brian
DOI：
10.1126/science.aaa4484
发表时间：
2015-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Das I;Krzyzosiak A;Schneider K;Wrabetz L;D'Antonio M;Barry N;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A
影响因子：
25
作者：
Lin, Wensheng;Popko, Brian
通讯作者：
Popko, Brian
影响因子：
30.8
作者：
Lappe-Siefke, C;Goebbels, S;Nave, KA
通讯作者：
Nave, KA
DOI：
10.1083/jcb.200502086
发表时间：
2005-05-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lin W;Harding HP;Ron D;Popko B
通讯作者：
Popko B