Dataset Information

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

ABSTRACT: Objective:Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the ?-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 ?-cell function are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the ?-cell and the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation.

Methods:We used isolated islets from mice deleted selectively in the ?-cell for Stard10 (?Stard10KO) 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.

Results:?Stard10KO 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 ?Stard10KO 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 ?Stard10KO islets.

Conclusion:Our data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis, and insulin processing.

SUBMITTER: Carrat GR

PROVIDER: S-EPMC7322359 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Carrat Gaelle R GR Haythorne Elizabeth E Tomas Alejandra A Haataja Leena L Müller Andreas A Arvan Peter P Piunti Alexandra A Cheng Kaiying K Huang Mutian M Pullen Timothy J TJ Georgiadou Eleni E Stylianides Theodoros T Amirruddin Nur Shabrina NS Salem Victoria V Distaso Walter W Cakebread Andrew A Heesom Kate J KJ Lewis Philip A PA Hodson David J DJ Briant Linford J LJ Fung Annie C H ACH Sessions Richard B RB Alpy Fabien F Kong Alice P S APS Benke Peter I PI Torta Federico F Teo Adrian Kee Keong AKK Leclerc Isabelle I Solimena Michele M Wigley Dale B DB Rutter Guy A GA

Molecular metabolism 20200513

<h4>Objective</h4>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 aff ...[more]

PMID: 32416313

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Project description:Germanos M1*. Yau B1*. Taper M1. An Y1. Yeoman C1. Wilson A1. Cattin-Ortolá J2. Maslar D3. Tong J1. Naghiloo S1. Needham E4. Diaz-Vegas A4. Larance M1. Thomas H5. Seidah NG6. von Blume J7. James DE4. Thorn P1. Ailion M2. Asensio C3. Kebede MA1. 1 School of Medical Sciences, Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia. 2 Department of Biochemistry, University of Washington, Seattle, WA USA. 3 Department of Biological Sciences, University of Denver, Denver, Colorado 80210, United States. 4 Discipline of Biochemistry and Molecular Biology, School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia. 5 Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Melbourne, Victoria, Australia. 6 Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada. 7 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.. *These authors contributed equally. Abstract Here we investigate the role of Cab45 in β-cell function and insulin secretory granule (ISG) biogenesis. Cab45 has been known as a ubiquitously expressed, soluble, trans-Golgi network (TGN) resident protein. We demonstrate its expression in pancreatic islets but not exocrine tissue, and localization in both Golgi and granular/vesicular compartments of primary β-cells. In INS1 cells, Cab45 is held in the cis-Golgi by a calcium-dependent mechanism but is capable of anterograde trafficking beyond the TGN. ISG biogenesis is maintained in Cab45 knockout INS1 cells which exhibit insulin hypersecretion due to dysregulated calcium homeostasis, leading to ISG depletion that is reinstated by rest at low glucose or Cab45 overexpression. Overexpressed Cab45 traffics directly into ISGs and increases biogenesis. Expression of a Cab45 variant that cannot bind calcium drives superior ISG rescue and has reduced ISG residency. In humans, anterograde Cab45 trafficking increases with worsening obesity, suggesting recruitment to drive cargo transit and support secretory output. Humans with type 2 diabetes, however, contain a greater proportion of Cab45-occupied ISGs and a loss of Golgi-localized Cab45 compared to non-diabetics. These insights position Cab45 as an exciting candidate for further investigation into mechanisms associated with β-cell compensation and failure.

Dataset Information

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

Publications

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

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