Rab26 Restricts Insulin Secretion Via Sequestering Synaptotagmin-1

Overview

Journal PLoS Biol

Specialty Biology

Date 2023 Jun 8

PMID 37289842

Authors

Ruijuan Zhuang

Yuxia Zhou

Ziyan Wang

Yating Cao

Jun Chen

Liju Xu

Yandan Ren

Yige Zheng

Ziheng Wei

Hantian Qiu

Liangcheng Li

Yang Han

Ye Yun

Xin Chen

Wanjin Hong

Tuanlao Wang

Affiliations

Soon will be listed here.

Abstract

Rab26 is known to regulate multiple membrane trafficking events, but its role in insulin secretion in pancreatic β cells remains unclear despite it was first identified in the pancreas. In this study, we generated Rab26-/- mice through CRISPR/Cas9 technique. Surprisingly, insulin levels in the blood of the Rab26-/- mice do not decrease upon glucose stimulation but conversely increase. Deficiency of Rab26 promotes insulin secretion, which was independently verified by Rab26 knockdown in pancreatic insulinoma cells. Conversely, overexpression of Rab26 suppresses insulin secretion in both insulinoma cell lines and isolated mouse islets. Islets overexpressing Rab26, upon transplantation, also failed to restore glucose homeostasis in type 1 diabetic mice. Immunofluorescence microscopy revealed that overexpression of Rab26 results in clustering of insulin granules. GST-pulldown experiments reveal that Rab26 interacts with synaptotagmin-1 (Syt1) through directly binding to its C2A domain, which interfering with the interaction between Syt1 and SNAP25, and consequently inhibiting the exocytosis of newcomer insulin granules revealed by TIRF microscopy. Our results suggest that Rab26 serves as a negative regulator of insulin secretion, via suppressing insulin granule fusion with plasma membrane through sequestering Syt1.

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