Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
Sci Rep. 2017 Mar 21;7(1):248. doi: 10.1038/s41598-017-00344-z.
Insulin secretion from pancreatic ß cells is a multistep process that requires the coordination of exocytotic proteins that integrate diverse signals. These include signals derived from metabolic control of post-translational SUMOylation and depolarization-induced rises in intracellular Ca. Here we show that tomosyn, which suppresses insulin exocytosis by binding syntaxin1A, does so in a manner which requires its SUMOylation. Glucose-dependent de-SUMOylation of tomosyn1 at K298 releases syntaxin1A and controls the amplification of exocytosis in concert with a recently-identified tomosyn1-interacting partner; the Ca-binding protein secretagogin, which dissociates from tomosyn1 in response to Ca-raising stimuli and is required for insulin granule trafficking and exocytosis downstream of Ca influx. Together our results suggest that tomosyn acts as a key signaling hub in insulin secretion by integrating signals mediated by metabolism-dependent de-SUMOylation and electrically-induced entry of Ca to regulate the availability of exocytotic proteins required for the amplification of insulin secretion.
胰岛β细胞的胰岛素分泌是一个多步骤的过程，需要协调将各种信号整合在一起的胞吐蛋白。这些信号包括代谢控制的翻译后 SUMO 化和去极化诱导的细胞内 Ca 升高。在这里，我们表明，通过结合 syntaxin1A 抑制胰岛素胞吐的 tomosyn 以需要其 SUMO 化的方式起作用。葡萄糖依赖性 tomosyn1 在 K298 的去 SUMO 化释放 syntaxin1A，并与最近鉴定的 tomosyn1 相互作用伙伴；钙结合蛋白 secretagogin 一起协同控制胞吐作用的放大，secretagogin 响应 Ca 升高刺激从 tomosyn1 解离，并且是胰岛素颗粒运输和 Ca 流入下游胞吐作用所必需的。总之，我们的研究结果表明，tomosyn 通过整合代谢依赖性去 SUMO 化和电诱导 Ca 进入调节胰岛素分泌放大所需的胞吐蛋白的可用性，作为胰岛素分泌的关键信号枢纽。
