CASK, APBA1, and STXBP1 collaborate during insulin secretion
CASK, APBA1, and STXBP1 collaborate during insulin secretion
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DOI：
10.1016/j.mce.2020.111076
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发表时间：
2020-11
影响因子：
4.1
通讯作者：
Kai Zhang;Tian-yuan Wang;Xingjing Liu;Qingzhao Yuan;Ting Xiao;Xiangjiang Yuan;Yijian Zhang;Li Yuan;Yao Wang
中科院分区：
文献类型：
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作者：
Kai Zhang;Tian-yuan Wang;Xingjing Liu;Qingzhao Yuan;Ting Xiao;Xiangjiang Yuan;Yijian Zhang;Li Yuan;Yao Wang
钙/钙调蛋白依赖性丝氨酸蛋白激酶（CASK）敲低减少胰岛素囊泡与细胞膜的对接。在这里，我们探索了胰岛素分泌过程中CASK与其他蛋白质的相互作用。利用免疫共沉淀、液相色谱-质谱和生物信息学分析，我们发现CASK、衔接蛋白X11 alpha（APBA 1）和突触融合蛋白结合蛋白1（STXBP 1）在胰岛素分泌过程中形成了三重复合物。CASK增强APBA 1-STXBP 1相互作用，并在胰岛素释放过程中介导它们从细胞质到质膜的运输。高脂肪酸刺激沿着CASK、APBA 1和STXBP 1表达减少胰岛素分泌;Caskoverexpression增强CASK/APBA 1/STXBP 1三方复合物功能，并因此可能挽救脂毒性诱导的胰岛素释放缺陷。总的来说，我们的结果说明了CASK在胰岛素颗粒胞吐中的功能，这拓宽了胰岛素分泌的潜在机制，并突出了CASK作为2型糖尿病（T2 DM）药物靶点的临床潜力。
Calcium/calmodulin-dependent serine protein kinase (CASK) knockdown reduces insulin vesicle docking to cell membranes. Here, we explored CASK interactions with other proteins during insulin secretion. Using co-immunoprecipitation, liquid chromatography-mass spectrometry and bioinformatic analysis, we identified that CASK, Adapter protein X11 alpha (APBA1), and Syntaxin binding protein 1 (STXBP1) formed tripartite complex during insulin secretion. CASK enhanced APBA1–STXBP1 interaction and mediated their traffic from cytoplasm to plasma membrane during insulin release. High fatty acid stimulation decreased insulin secretion along with CASK, APBA1, and STXBP1 expression;Caskoverexpression enhanced CASK/APBA1/STXBP1 tripartite complex function, and may thereby rescue lipotoxicity-induced insulin-release defects. Collectively, our results illustrated the function of CASK in insulin granules exocytosis, which broadens the underlying mechanism of insulin secretion and highlights the clinical potential of CASK as a drug target of type 2 Diabetes Mellitus (T2DM).