@article{carrat_type_2020,
	title = {The type 2 diabetes gene product {STARD}10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis},
	rights = {© 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 {STARD}10 locus are associated with lowered {STARD}10 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 {STARD}10 regulates β-cell function, are not understood. The aim of this study was to identify the lipids transported and affected by {STARD}10 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 (β{StarD}10KO) and performed electron microscopy, pulse-chase, {RNA} sequencing and lipidomic analyses. Proteomic analysis of {STARD}10 binding partners was executed in {INS}1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified {STARD}10 protein. Results: β{StarD}10KO 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 β{StarD}10KO 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 {PIP}4K2C was also identified as a {STARD}10 binding partner. {STARD}10 bound to inositides phosphorylated at the 3′ position and solution of the crystal structure of {STARD}10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides. Conclusion: Our data indicate that {STARD}10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis and insulin processing.{\textless}/p{\textgreater}},
	pages = {2020.03.25.007286},
	journaltitle = {{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.},
	urldate = {2020-03-31},
	date = {2020-03-26},
	langid = {english},
	note = {Publisher: Cold Spring Harbor Laboratory
Section: New Results},
	keywords = {{WP}4},
}