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© 2023 Zhuang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Rab26 restricts insulin secretion via sequestering Synaptotagmin-1
Author
Zhuang, Ruijuan; Zhou, Yuxia; Wang, Ziyan; Cao, Yating; Chen, Jun; Xu, Liju; Ren, Yandan; Zheng, Yige; Wei, Ziheng; Qiu, Hantian; Li, Liangcheng; Yang, Han; Ye Yun; Chen, Xin; Hong, Wanjin; Tuanlao Wang https://orcid.org/0000-0001-5375-1615
First page
e3002142
Section
Research Article
Publication year
2023
Publication date
Jun 2023
Publisher
Public Library of Science
ISSN
15449173
e-ISSN
15457885
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2838338814
Copyright
© 2023 Zhuang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.