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Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesised insulin receptors to the cell surface.
Molecular Biology of the Cell ( IF 3.3 ) Pub Date : 2020-09-02 , DOI: 10.1091/mbc.e18-01-0013
Max Brown 1, 2, 3 , Samantha Dainty 1, 2, 3 , Natalie Strudwick 1, 2, 3 , Adina D Mihai 1, 2, 3 , Jamie N Watson 1, 2, 3 , Robina Dendooven 1, 2, 3 , Adrienne W Paton 4 , James C Paton 4 , Martin Schröder 1, 2, 3
Affiliation  

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates a signalling network known as the unfolded protein response (UPR). Here we characterise how ER stress and the UPR inhibit insulin signalling. We find that ER stress inhibits insulin signalling by depleting the cell surface population of the insulin receptor. ER stress inhibits proteolytic maturation of insulin proreceptors by interfering with transport of newly synthesised insulin proreceptors from the ER to the plasma membrane. Activation of AKT, a major target of the insulin signalling pathway, by a cytosolic, membrane-bound chimera between the AP20187-inducible FV2E dimerisation domain and the cytosolic protein tyrosine kinase domain of the insulin receptor was not affected by ER stress. Hence, signalling events in the UPR, such as activation of the JNK MAP kinases or the pseudokinase TRB3 by the ER stress sensors IRE1α and PERK, do not contribute to inhibition of signal transduction in the insulin signalling pathway. Indeed, pharmacologic inhibition and genetic ablation of JNKs, as well as silencing of expression of TRB3, did not restore insulin sensitivity or rescue processing of newly synthesised insulin receptors in ER-stressed cells.



中文翻译:

内质网应激通过抑制新合成的胰岛素受体向细胞表面的输送而导致胰岛素抵抗。

内质网 (ER) 中未折叠蛋白的积累会导致 ER 应激,并激活称为未折叠蛋白反应 (UPR) 的信号网络。在这里,我们描述了 ER 应激和 UPR 如何抑制胰岛素信号传导。我们发现内质网应激通过消耗胰岛素受体的细胞表面群来抑制胰岛素信号传导。内质网应激通过干扰新合成的胰岛素前体从内质网转运到质膜来抑制胰岛素前体的蛋白水解成熟。AP20187 诱导的 F V 2E 二聚化结构域和胰岛素受体的胞质蛋白酪氨酸激酶结构域之间的胞质膜结合嵌合体对 AKT(胰岛素信号传导通路的主要靶标)的激活不受 ER 应激的影响。因此,UPR 中的信号事件,例如 ER 应激传感器 IRE1α 和 PERK 激活 JNK MAP 激酶或假激酶 TRB3,不会有助于抑制胰岛素信号传导途径中的信号转导。事实上,JNK 的药理抑制和基因消除,以及 TRB3 表达的沉默,并没有恢复胰岛素敏感性或挽救 ER 应激细胞中新合成的胰岛素受体的加工。

更新日期:2020-09-02
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