Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, 210009, China.
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210009, China.
Mol Cell Endocrinol. 2021 Jan 15;520:111076. doi: 10.1016/j.mce.2020.111076. Epub 2020 Nov 4.
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) 敲低减少胰岛素囊泡向细胞膜的对接。在这里，我们探讨了 CASK 在胰岛素分泌过程中与其他蛋白质的相互作用。通过免疫共沉淀、液相色谱-质谱联用和生物信息学分析，我们发现 CASK、衔接蛋白 X11α (APBA1) 和突触结合蛋白 1 (STXBP1) 在胰岛素分泌过程中形成三聚体复合物。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向质膜的运输。高脂肪酸刺激会降低胰岛素分泌，同时降低 CASK、APBA1 和 STXBP1 的表达；Cask 过表达增强了 CASK/APBA1/STXBP1 三聚体复合物的功能，从而可能挽救脂毒性诱导的胰岛素释放缺陷。总之，我们的结果说明了 CASK 在胰岛素颗粒胞吐作用中的功能，这拓宽了胰岛素分泌的潜在机制，并强调了 CASK 作为 2 型糖尿病 (T2DM) 药物靶点的临床潜力。
