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; Cask overexpression 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).

钙/钙调蛋白依赖性丝氨酸蛋白激酶 (CASK) 敲低可减少胰岛素囊泡与细胞膜的对接。在这里，我们探讨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-质谱联用和生物信息分析，我们鉴定出CASK、接头蛋白X11α（APBA1）和突触蛋白结合蛋白1（STXBP1）在胰岛素分泌过程中形成三联复合物。 CASK 增强了 APBA1-STXBP1 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。高脂肪酸刺激会降低胰岛素分泌以及 CASK、APBA1 和 STXBP1 的表达； Cask过表达增强了 CASK/APBA1/STXBP1 三方复合体功能，从而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 在胰岛素颗粒胞吐作用中的功能，拓宽了胰岛素分泌的潜在机制，并凸显了 CASK 作为 2 型糖尿病 (T2DM) 药物靶点的临床潜力。