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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 its effect on proinsulin processing and insulin granule biogenesis and maturation. Methods We used isolated islets from mice deleted selectively in the β-cell for Stard10 (β StarD10 KO) 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 β StarD10 KO 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 StarD10 KO 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. * BUDE : Bristol University Docking Engine GFP : Green Fluorescent Protein GWAS : Genome Wide Association Study KATP : ATP-sensitive K+ channels HRP : Horseradish Peroxidase Kir6.2 : Kcnj11 : Potassium Inwardly Rectifying Channel Subfamily J Member 11 KOMP : NIH Knock-Out Mouse Project ICP/MS : Inductively coupled plasma mass spectrometry IMPC : International Mouse Phenotyping Consortium LPC : Lysophosphatidylcholine MBP : Maltose Binding Protein PC : Phosphatidylcholine PE : Phosphatidylethanolamine PI : Phosphatidylinositol PI(3)P : Phosphatidylinositol 3-phosphate PI(4,5)P2 : PIP2, Phosphatidylinositol 4,5-bisphosphate PI(5)P : Phosphatidylinositol 5-phosphate PIP : phosphatidylinositol phosphate, phosphatidylinositide Pip4k2c : phosphatidylinositol 5-phosphate 4-kinase type-2 gamma Pirt : phosphoinositide-interacting regulator of transient receptor potential channels RNAseq : RNA sequencing Ptbp1 : Polypyrimidine tract-binding protein 1 Slc30a8 : ZnT8, Solute Carrier Family 30 Member 8 SNARE : Soluble N-ethylmaleimide sensitive factor Attachment protein Receptor STARD10 : StAR Related Lipid Transfer Domain Containing 10 Syt1 : Synaptotagmin 1 Sytl4 : synaptotagmin-like 4, granuphilin TMT : Tandem Mass Tag TRP : Transient receptor potential

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