Insulin is packaged into secretory granules that depart the Golgi and undergo a maturation process that involves changes in the protein and lipid composition of the granules. Here, we show that insulin secretory granules form physical contacts with the endoplasmic reticulum and that the lipid exchange protein oxysterol-binding protein (OSBP) is recruited to these sites in a Ca2+-dependent manner. OSBP binding to insulin granules is positively regulated by phosphatidylinositol-4 (PI4)-kinases and negatively regulated by the PI4 phosphate (PI(4)P) phosphatase Sac2. Loss of Sac2 results in excess accumulation of cholesterol on insulin granules that is normalized when OSBP expression is reduced, and both acute inhibition and small interfering RNA (siRNA)-mediated knockdown of OSBP suppress glucose-stimulated insulin secretion without affecting insulin production or intracellular Ca2+ signaling. In conclusion, we show that lipid exchange at endoplasmic reticulum (ER)-granule contact sites is involved in the exocytic process and propose that these contacts act as reaction centers with multimodal functions during insulin granule maturation.
Institut(e)Institute for Pancreatic Beta Cell Research (IPI)
FörderungenEFSD Swiss State Secretariat for Education Research and Innovation (SERI) Innovative Medicines Initiative 2 Joint Undertaking German Ministry for Education and Research (BMBF) German Center for Diabetes Research EFSD/Lilly Familjen Ernfors stiftelse Magnus Bergwalls stiftelse Ake Wibergs stiftelse Novo Nordisk Foundation Diabetes UK Carl Gustav Carus Faculty of Medicine at TU Dresden UKRI COVID-19 Grant Extension Allocation (CoA) UKRI Medical Research Council Swedish national strategic grant initiative Excellence of Diabetes Research in Sweden (EXODIAB) Novo-Nordisk Foundation Nils Erik Holmsten's Foundation Family Ernfors Foundation Integrated Biological Imaging Network (IBIN) Diabetes Wellness Foundation Commonwealth Swedish Diabetes Foundation Eli Lilly Swedish Research Council