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

DOI: 10.1016/j.molmet.2020.101015 DOI Help

Authors: Gaelle R. Carrat (Imperial College London) , Elizabeth Haythorne (Imperial College London) , Alejandra Tomas (Imperial College London) , Leena Haataja (University of Michigan) , Andreas Müller (TU Dresden; German Center for Diabetes Research (DZD e.V.); Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)) , Peter Arvan (University of Michigan) , Alexandra Piunti (Imperial College London; Lille 1 University - Science and Technology) , Kaiying Cheng (Imperial College London) , Mutian Huang (Imperial College London,) , Timothy J. Pullen (Imperial College London; King’s College London) , Eleni Georgiadou (Imperial College London) , Theodoros Stylianides (Loughborough University) , Nur Shabrina Amirruddin (Institute of Molecular and Cell Biology (IMCB), A*STAR; National University of Singapore) , Victoria Salem (Imperial College London) , Walter Distaso (Imperial College London) , Andrew Cakebread (King’s College London) , Kate J. Heesom (University of Bristol) , Philip A. Lewis (University of Bristol) , David J. Hodson (Birmingham Health Partners; University of Birmingham; University of Nottingham) , Linford J. Briant (University of Oxford) , Annie C. H. Fung (The Chinese University of Hong Kong) , Richard B. Sessions (University of Bristol) , Fabien Alpy (Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Institut National de la Santé et de la Recherche Médicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Université de Strasbourg) , Alice P. S. Kong (The Chinese University of Hong Kong) , Peter I. Benke (National University of Singapore) , Federico Torta (National University of Singapore) , Adrian Kee Keong Teo (Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR; National University of Singapore) , Isabelle Leclerc (Imperial College London) , Michele Solimena (University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden; Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, University Hospital Carl Gustav Carus and Faculty of Medicine of the TU Dresden; German Center for Diabetes Research (DZD e.V.); Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) , Dale B. Wigley (Imperial College London) , Guy A. Rutter (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Metabolism

State: Published (Approved)
Published: May 2020

Open Access Open Access

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 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 INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were 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. 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 phosphatidyl inositol 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.

Journal Keywords: Type 2 diabetes; pancreatic β-cell; lipid transporter; insulin granule biogenesisphos; phoinositides

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography


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