RILP Restricts Insulin Secretion Through Mediating Lysosomal Degradation of Proinsulin
RILP Restricts Insulin Secretion Through Mediating Lysosomal Degradation of Proinsulin
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RILP 通过介导胰岛素原的溶酶体降解来限制胰岛素分泌
DOI：
10.2337/db19-0086
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发表时间：
2020-01-01
期刊：
影响因子：
7.7
通讯作者：
Wang, Tuanlao
中科院分区：
文献类型：
--
作者：
Zhou, Yuxia;Liu, Zhiyu;Wang, Tuanlao
胰岛素分泌受到细胞膜运输的严格调控。RILP （Rab7相互作用溶酶体蛋白）调节内吞运输，但其在胰岛素分泌中的作用尚未被研究。在这项研究中，我们发现RILP的过表达抑制了β细胞系和新分离的胰岛的胰岛素分泌。因此，胰岛中RILP的表达抑制了移植后1型糖尿病小鼠恢复葡萄糖稳态的能力。与生理相关的是，RILP在糖尿病小鼠胰岛中的表达上调。在机制上，RILP的过表达诱导胰岛素颗粒聚集，减少β-细胞中含胰岛素原颗粒的数量，显著促进胰岛素原降解。相反，RILP消耗维持胰岛素原并增加胰岛素分泌。由RILP表达引起的胰岛素原降解被溶酶体抑制剂抑制，并且依赖于rab7。最后，我们发现RILP与胰岛素颗粒相关的Rab26相互作用，限制胰岛素分泌。本研究提出了调节胰岛素分泌的新途径，并机械地证明了RILP通过介导胰岛素原酶体降解来调节胰岛素分泌的新功能。
Insulin secretion is tightly regulated by membrane trafficking. RILP (Rab7 interacting lysosomal protein) regulates the endocytic trafficking, but its role in insulin secretion has not been investigated. In this study, we found that overexpression of RILP inhibited insulin secretion in both the β-cell lines and freshly isolated islets. Consequently, the expression of RILP in islets suppressed the ability to recover the glucose homeostasis in type 1 diabetes mice upon transplantation. Of physiological relevance is that RILP expression was upregulated in the diabetic mouse islets. Mechanistically, overexpression of RILP induced insulin granule clustering, decreased the number of proinsulin-containing granules in β-cells, and significantly promoted proinsulin degradation. Conversely, RILP depletion sustained proinsulin and increased insulin secretion. The proinsulin degradation induced by RILP expression was inhibited by lysosomal inhibitors and was Rab7-dependent. Finally, we showed that RILP interacts with insulin granule–associated Rab26 to restrict insulin secretion. This study presents a new pathway regulating insulin secretion and mechanically demonstrates a novel function of RILP in modulating insulin secretion through mediating the lysosomal degradation of proinsulin.