MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.
MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.
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DOI：
10.1038/ncomms12639
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发表时间：
2016-08-31
影响因子：
16.6
通讯作者：
Wajapeyee, Narendra
中科院分区：
文献类型：
--
作者：
Nagarajan, Arvindhan;Petersen, Max C.;Nasiri, Ali R.;Butrico, Gina;Fung, Annie;Ruan, Hai-Bin;Kursawe, Romy;Caprio, Sonia;Thibodeau, Jacques;Bourgeois-Daigneault, Marie-Claude;Sun, Lisha;Gao, Guangping;Bhanot, Sanjay;Jurczak, Michael J.;Green, Michael R.;Shulman, Gerald I.;Wajapeyee, Narendra
胰岛素抵抗是2型糖尿病（T2D）的关键驱动因素，其特征在于胰岛素受体（INSR）信号传导缺陷。虽然表面INSR下调是胰岛素抵抗的一个公认因素，但其潜在的分子机制仍不清楚。在这里，我们表明，E3泛素连接酶MARCH 1通过降解细胞表面INSR损害细胞胰岛素的作用。使用大规模的RNA干扰筛选，我们确定MARCH 1作为INSR信号传导的负调节因子。March 1功能丧失增强小鼠肝脏胰岛素敏感性，而March 1过表达损害小鼠肝脏胰岛素敏感性。MARCH 1泛素化INSR以降低细胞表面INSR水平，但与其他INSR泛素连接酶不同，MARCH 1在基础状态下而不是在胰岛素刺激后起作用。因此，MARCH 1可能有助于设定胰岛素信号传导的基础增益。MARCH 1表达在肥胖人的白色脂肪组织中增加，表明MARCH 1有助于T2 D的病理生理学，并且可能是新的治疗靶点。 在胰岛素抵抗中，细胞表面的胰岛素受体水平降低，原因尚不完全清楚。在这里，作者确定E3泛素连接酶MARCH 1作为基础胰岛素受体表面水平的直接调节剂，因此，胰岛素信号。
Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target. Insulin receptor levels at the cell surface are reduced in insulin resistance, for reasons that are not fully understood. Here, the authors identify the E3 ubiquitin ligase MARCH1 as a direct regulator of basal insulin receptor surface levels and, therefore, insulin signalling.
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影响因子：
3.3
作者：
Eyster CA;Cole NB;Petersen S;Viswanathan K;Früh K;Donaldson JG
通讯作者：
Donaldson JG
影响因子：
7.7
作者：
Kursawe R;Eszlinger M;Narayan D;Liu T;Bazuine M;Cali AM;D'Adamo E;Shaw M;Pierpont B;Shulman GI;Cushman SW;Sherman A;Caprio S
通讯作者：
Caprio S
影响因子：
3.7
作者：
Li W;Bengtson MH;Ulbrich A;Matsuda A;Reddy VA;Orth A;Chanda SK;Batalov S;Joazeiro CA
通讯作者：
Joazeiro CA
影响因子：
4.8
作者：
Corcoran, Kathleen;Jabbour, Maurice;Lybarger, Lonnie
通讯作者：
Lybarger, Lonnie
DOI：
10.1126/science.1199498
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hsu PP;Kang SA;Rameseder J;Zhang Y;Ottina KA;Lim D;Peterson TR;Choi Y;Gray NS;Yaffe MB;Marto JA;Sabatini DM
通讯作者：
Sabatini DM