IP(6)-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion.
IP(6)-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion.
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IP6 辅助的 CSN-COP1 竞争调节 CRL4-ETV5 蛋白水解检查点以保护葡萄糖诱导的胰岛素分泌
DOI：
10.1038/s41467-021-22941-3
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发表时间：
2021-04-28
影响因子：
16.6
通讯作者：
Rao F
中科院分区：
文献类型：
--
作者：
Lin H;Yan Y;Luo Y;So WY;Wei X;Zhang X;Yang X;Zhang J;Su Y;Yang X;Zhang B;Zhang K;Jiang N;Chow BKC;Han W;Wang F;Rao F
COP 1和COP 9信号体（CSN）分别是CRL 4 E3连接酶的底物受体和去卷曲酶。它们在功能上如何相互作用尚不清楚。在这里，我们发现COP 1-CSN拮抗作用在葡萄糖诱导的胰岛素分泌。IP 6（CSN辅因子）结合部分中断的杂合Csn 2 WT/K70 E小鼠显示先天性高胰岛素血症和胰岛素抵抗。这是由于Cul 4 neddylation，CRL 4COP 1 E3装配和ETV 5（肥胖相关的胰岛素分泌转录抑制因子）泛素化增加所致。高血压调节CRL 4-CSN相对于CRL 4COP 1组装以促进ETV 5降解。过度的ETV 5降解是Csn 2 WT/K70 E、高脂饮食处理的和ob/ob小鼠的标志。CRL neddylation抑制剂Pevonedistat/MLN 4924可稳定ETV 5并纠正这些小鼠的高胰岛素血症和肥胖/糖尿病表型。这些观察结果扩展到人类胰岛和EndoC-βH1细胞。因此，CRL 4C 0 P1-ETV 5蛋白水解检查点许可GSIS通过IP 6辅助的CSN-C 0 P1竞争来保障。IP 6-CSN-CRL 4COP 1-ETV 5轴的失调是高胰岛素血症的基础，可以进行干预以降低肥胖和糖尿病风险。胰岛素信号传导的介导剂是介导蛋白质降解的cullin-RING泛素连接酶（CRL）的靶点，但蛋白质降解在胰岛素信号传导中的作用尚不完全清楚。在这里，作者确定了一个葡萄糖响应性的CRL 4-COP 1-ETV 5蛋白水解轴，它促进胰岛素分泌，并在低血糖时受到抑制。
COP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1–CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2WT/K70E mice with partially disrupted binding of IP6, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4COP1 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4COP1 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2WT/K70E, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4COP1-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP6-assisted CSN-COP1 competition. Deregulation of the IP6-CSN-CRL4COP1-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk. Mediators of insulin signalling are targets of cullin-RING ubiquitin ligases (CRL) that mediate protein degradation, but the role of protein degradation in insulin signalling is incompletely understood. Here, the authors identified a glucose-responsive CRL4-COP1-ETV5 proteolytic axis that promotes insulin secretion, and is inhibited under hypoglycemia.
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影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
胰岛素抵抗和高胰岛素血症：没有另一个人。
影响因子：
16.2
作者：
Kim, Sun H.;Reaven, Gerald M.
通讯作者：
Reaven, Gerald M.
影响因子：
5.2
作者：
Erion K;Corkey BE
通讯作者：
Corkey BE
DOI：
10.1146/annurev-pharmtox-010715-103507
发表时间：
2017-01-06
影响因子：
12.5
作者：
Bondeson DP;Crews CM
通讯作者：
Crews CM
影响因子：
8.2
作者：
Gutierrez-Aguilar, Ruth;Kim, Dong-Hoon;Casimir, Marina;Dai, Xiao-Qing;Pfluger, Paul T.;Park, Jongsun;Haller, April;Donelan, Elizabeth;Park, Jisoo;D'Alessio, David;Woods, Stephen C.;MacDonald, Patrick E.;Seeley, Randy J.
通讯作者：
Seeley, Randy J.