RACK1 在调节胰岛β细胞葡萄糖刺激的 IRE1α 激活中起关键作用。
A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells.
机构信息
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
出版信息
Sci Signal. 2010 Jan 26;3(106):ra7. doi: 10.1126/scisignal.2000514.
Autophosphorylation of inositol-requiring enzyme 1alpha (IRE1alpha) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic beta cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1alpha in a glucose-stimulated or endoplasmic reticulum (ER) stress-responsive manner in pancreatic beta cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1alpha by PP2A, thereby inhibiting glucose-stimulated IRE1alpha activation and attenuating IRE1alpha-dependent increases in insulin production. Moreover, IRE1alpha activation was increased and RACK1 abundance was decreased in a mouse model of diabetes. Thus, our findings demonstrate that RACK1 functions as a key component in regulating the IRE1alpha signaling pathway in pancreatic beta cells.
肌醇需求酶 1α（IRE1α）的自身磷酸化是其激活所必需的，这会引发细胞未折叠蛋白反应（UPR），并与胰腺β细胞中的胰岛素生物合成在功能上相关。我们发现支架蛋白激活的 C 激酶 1（RACK1）在胰腺β细胞和原代胰岛中以葡萄糖刺激或内质网（ER）应激反应的方式与 IRE1α相互作用。RACK1 介导了包含 IRE1α、RACK1 和蛋白磷酸酶 2A（PP2A）的复合物的葡萄糖诱导组装，以促进 PP2A 对 IRE1α的去磷酸化，从而抑制葡萄糖刺激的 IRE1α激活并减弱 IRE1α依赖性胰岛素产生的增加。此外，在糖尿病小鼠模型中，IRE1α的激活增加，而 RACK1 的丰度降低。因此，我们的研究结果表明，RACK1 作为调节胰腺β细胞中 IRE1α信号通路的关键组成部分发挥作用。
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