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Panagiotou, S.* ; Tan, K.W.* ; Nguyen, P.M.* ; Müller, A. ; Oqua, A.I.* ; Tomas, A.* ; Wendt, A.* ; Eliasson, L.* ; Tengholm, A.* ; Solimena, M. ; Idevall-Hagren, O.*

OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion.

Cell Rep. 43:113992 (2024)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cp: Cell Biology ; Cp: Metabolism ; Ca(2+) ; Osbp ; Beta Cell ; Endoplasmic Reticulum ; Insulin ; Membrane Contact Sites ; Ph ; Phophatidylinositol 4-phosphate ; Secretory Granule; Pancreatic Beta-cells; Oxysterol-binding-protein; Phosphatidylinositol 4-phosphate; Ca2+ Channels; Ph Domains; Glucose; Calcium; Localization; Sac2/inpp5f; Exocytosis

ISSN (print) / ISBN 2211-1247

e-ISSN 2211-1247

Journal Cell Reports

Quellenangaben Volume: 43, Issue: 4, Article Number: 113992

Publisher Cell Press

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Pancreatic Beta Cell Research (IPI)

Grants EFSD
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