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.

中文翻译：

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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

胰岛素分泌受到膜运输的严格调控。RILP（Rab7 相互作用溶酶体蛋白）调节内吞运输，但尚未研究其在胰岛素分泌中的作用。在这项研究中，我们发现 RILP 的过表达抑制了 β 细胞系和新鲜分离的胰岛中的胰岛素分泌。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。生理相关性是 RILP 表达在糖尿病小鼠胰岛中上调。从机制上讲，RILP 的过表达会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，并显着促进胰岛素原降解。相反，RILP 耗竭维持胰岛素原和增加胰岛素分泌。RILP 表达诱导的胰岛素原降解被溶酶体抑制剂抑制并且是 Rab7 依赖性的。最后，我们发现 RILP 与胰岛素颗粒相关的 Rab26 相互作用以限制胰岛素分泌。该研究提出了一种调节胰岛素分泌的新途径，并机械地证明了 RILP 通过介导溶酶体降解胰岛素原来调节胰岛素分泌的新功能。