%0 Journal Article
%T The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis
%P 2020.03.25.007286
%* © 2020, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/
%U https://www.biorxiv.org/content/10.1101/2020.03.25.007286v2
%X <p>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 beta-cell and its effect on proinsulin processing and insulin granule biogenesis and maturation. Methods: We used isolated islets from mice deleted selectively in the beta-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. Amongst the differentially expressed genes in βStarD10KO islets, expression of the phosphoinositide binding proteins Pirt and Synaptotagmin 1 were decreased while lipidomic analysis demonstrated changes in phosphatidyl inositol levels. The inositol lipid kinase PIP4K2C was also identified as a STARD10 binding partner. STARD10 bound to inositides phosphorylated at the 3′ position and solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides. Conclusion: Our data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis and insulin processing.</p>
%G en
%J bioRxiv
%A Carrat, Gaelle R.
%A Haythorne, Elizabeth
%A Tomas, Alejandra
%A Haataja, Leena
%A Mueller, Andreas
%A Arvan, Peter
%A Piunti, Alexandra
%A Cheng, Kaiying
%A Huang, Mutian
%A Pullen, Timothy
%A Georgiadou, Eleni
%A Stylianides, Theodoros
%A Amirruddin, Nur Shabrina
%A Salem, Victoria
%A Distaso, Walter
%A Cakebread, Andrew
%A Heesom, Kate J.
%A Lewis, Philip A.
%A Hodson, David
%A Briant, Linford J.
%A Fung, Annie C. H.
%A Sessions, Richard B.
%A Alpy, Fabien
%A Kong, Alice P. S.
%A Benke, Peter I.
%A Torta, Federico
%A Teo, Adrian Kee Keong
%A Leclerc, Isabelle
%A Solimena, Michele
%A Wigley, Dale B.
%A Rutter, Guy A.
%D 2020-03-26
%K WP4