Abstract
ObjectiveRisk 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 the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation. MethodsWe 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 the INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay was performed on purified STARD10 protein. ResultsβStard10KO 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. The 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 phosphatidylinositol 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. ConclusionOur data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis, and insulin processing.
Highlights
Diabetes mellitus is characterised by high blood glucose and currently affects around 8.5% of the population worldwide
B-celleb-cell connections allow coordinated insulin secretion through the propagation of Ca2þ and other signals [3e5], a process impaired by glucolipotoxicity [6] and affected by genes implicated in diabetes risk through genome-wide association studies (GWAS) such as ADCY5 [7] and TCF7L2 [8]
Stard10 deletion affects dense core granule ultrastructure As an initial approach to determining the target membranes for STARD10 action, we first explored the impact of deleting the Stard10 gene on b-cell ultrastructure
Summary
Diabetes mellitus is characterised by high blood glucose and currently affects around 8.5% of the population worldwide. B-celleb-cell connections allow coordinated insulin secretion through the propagation of Ca2þ and other signals [3e5], a process impaired by glucolipotoxicity [6] and affected by genes implicated in diabetes risk through genome-wide association studies (GWAS) such as ADCY5 [7] and TCF7L2 [8]. We have recently examined a T2D-associated locus adjacent to STARD10 on chromosome 11q13 [9,10] Risk variants at this locus were associated with a decrease in STARD10 mRNA in human islets, with no concomitant change in the liver. Providing further compelling evidence for STARD10 as an “effector” gene, mice deleted for Stard in the b-cell recapitulated the features observed in the human carriers of the risk allele, with an increase in fed glycemia and a decrease in the plasma proinsulin:insulin ratio. We reveal an unexpected role for STARD10 in binding inositol phospholipids which may contribute to both secretory granule biogenesis and intracellular signalling
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