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The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis

Authors :
Gaelle R. Carrat
Elizabeth Haythorne
Alejandra Tomas
Leena Haataja
Andreas Müller
Peter Arvan
Alexandra Piunti
Kaiying Cheng
Mutian Huang
Timothy J. Pullen
Eleni Georgiadou
Theodoros Stylianides
Nur Shabrina Amirruddin
Victoria Salem
Walter Distaso
Andrew Cakebread
Kate J. Heesom
Philip A. Lewis
David J. Hodson
Linford J. Briant
Annie C.H. Fung
Richard B. Sessions
Fabien Alpy
Alice P.S. Kong
Peter I. Benke
Federico Torta
Adrian Kee Keong Teo
Isabelle Leclerc
Michele Solimena
Dale B. Wigley
Guy A. Rutter
Source :
Molecular Metabolism, Vol 40, Iss , Pp 101015- (2020)
Publication Year :
2020
Publisher :
Elsevier, 2020.

Abstract

Objective: Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the β-cell, impaired glucose-induced insulin secretion, and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids and thus the pathways through which STARD10 regulates β-cell function are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation. Methods: We used isolated islets from mice deleted selectively in the β-cell for Stard10 (βStard10KO) and performed electron microscopy, pulse-chase, RNA sequencing, and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in the INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay was performed on purified STARD10 protein. Results: βStard10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased versus wild-type islets. The solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides, and STARD10 was shown to bind to inositides phosphorylated at the 3’ position. Lipidomic analysis of βStard10KO islets demonstrated changes in phosphatidylinositol levels, and the inositol lipid kinase PIP4K2C was identified as a STARD10 binding partner. Also consistent with roles for STARD10 in phosphoinositide signalling, the phosphoinositide-binding proteins Pirt and Synaptotagmin 1 were amongst the differentially expressed genes in βStard10KO islets. Conclusion: Our data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis, and insulin processing.

Details

Language :
English
ISSN :
22128778
Volume :
40
Issue :
101015-
Database :
Directory of Open Access Journals
Journal :
Molecular Metabolism
Publication Type :
Academic Journal
Accession number :
edsdoj.075506f07a044c31be2e44b42ccc2527
Document Type :
article
Full Text :
https://doi.org/10.1016/j.molmet.2020.101015