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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 43, Heft: 4, Seiten: , Artikelnummer: 113992 Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pancreatic Islet Research (IPI)
POF Topic(s) 90000 - German Center for Diabetes Research
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502600-001
Förderungen 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
DOI 10.1016/j.celrep.2024.113992
WOS ID 001215101800001
Scopus ID 85188807080
PubMed ID 38536815
Erfassungsdatum 2024-05-21
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