@article{carrat_type_2020, title = {The type 2 diabetes gene product {STARD10} is a phosphoinositide binding protein that controls insulin secretory granule biogenesis}, copyright = {© 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/}, url = {https://www.biorxiv.org/content/10.1101/2020.03.25.007286v2}, doi = {10.1101/2020.03.25.007286}, abstract = {{\textless}p{\textgreater}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.{\textless}/p{\textgreater}}, language = {en}, urldate = {2020-03-31}, journal = {bioRxiv}, author = {Carrat, Gaelle R. and Haythorne, Elizabeth and Tomas, Alejandra and Haataja, Leena and Mueller, Andreas and Arvan, Peter and Piunti, Alexandra and Cheng, Kaiying and Huang, Mutian and Pullen, Timothy and Georgiadou, Eleni and Stylianides, Theodoros and Amirruddin, Nur Shabrina and Salem, Victoria and Distaso, Walter and Cakebread, Andrew and Heesom, Kate J. and Lewis, Philip A. and Hodson, David and Briant, Linford J. and Fung, Annie C. H. and Sessions, Richard B. and Alpy, Fabien and Kong, Alice P. S. and Benke, Peter I. and Torta, Federico and Teo, Adrian Kee Keong and Leclerc, Isabelle and Solimena, Michele and Wigley, Dale B. and Rutter, Guy A.}, month = mar, year = {2020}, note = {Publisher: Cold Spring Harbor Laboratory Section: New Results}, keywords = {WP4}, pages = {2020.03.25.007286}, }