The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Risk alleles for type 2 diabetes at the <jats:italic>STARD10</jats:italic> locus are associated with lowered <jats:italic>STARD10</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used isolated islets from mice deleted selectively in the β-cell for <jats:italic>Stard10</jats:italic> (β<jats:italic>StarD10</jats:italic>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>β<jats:italic>StarD10</jats:italic>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<jats:italic>StarD10</jats:italic>KO islets, expression of the phosphoinositide binding proteins <jats:italic>Pirt</jats:italic> and <jats:italic>Synaptotagmin 1</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis and insulin processing.</jats:p></jats:sec>

Loci for insulin processing and secretion provide insight into type 2 diabetes risk

“…Both STARD10 and ARAP1 are highly expressed in islets, with iESI scores of 9 and 7, respectively. The strength and direction of association between proinsulin and STARD10 were consistent with the evidence that STARD10 influences insulin granule biosynthesis and insulin processing by binding to phosphatidylinositides; beta cell deletion of Stard10 in mice led to impaired insulin secretion while overexpression of Stard10 improved glucose tolerance in high fat-fed animals 88,89 .…”

Genetic evidence for a causal relationship between type 2 diabetes and peripheral artery disease in both Europeans and East Asians

“…Moreover, protein-protein interaction analysis provided further evidence for common mechanisms shared between Europeans and East Asians by revealing gene-gene interactions underlying the comorbidity of T2D and PAD, specifically the interactions between STARD10 (European-specific) and AP3S2 (East Asian-specific) and between KCNJ11 (European-specific) and KCNQ1 (East Asian-specific). In the context of the interaction of STARD10 (European-specific) and AP3S2 (East Asian-specific), STARD10 is a phospholipid transfer protein whose expression in isolated pancreatic islets has been found to influence the production and processing of insulin in the mouse [92]. Prior studies indicated that STARD10 harbors SNPs associated with T2D [93,94].…”

Normal and defective pathways in biogenesis and maintenance of the insulin storage pool

“…159). The formation and maturation of insulin granules involve a complex set of processes that coordinate ionic control of the organelle interior (160,161), acquisition of competence for stimulus-dependent secretion (162,163), enzymatic processing of proinsulin (164,165), packaging (protein condensation) (166), and membrane trafficking and lipid modification (167)(168)(169)(170), as well as stability of the organelle during its intracellular transport through the cytoplasm (171-173); many of these steps are interconnected, and they are ultimately transcriptionally orchestrated (174). For example, the peripheral membrane protein HID-1 is thought to support proinsulin-to-insulin conversion that is synchronized with other steps of insulin secretory granule maturation (175).…”