OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion
(2024) In Cell Reports 43(4).- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2024-04-23
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- beta cell, Ca, CP: Cell biology, CP: Metabolism, endoplasmic reticulum, insulin, membrane contact sites, OSBP, pH, phophatidylinositol 4-phosphate, secretory granule
- in
- Cell Reports
- volume
- 43
- issue
- 4
- article number
- 113992
- publisher
- Cell Press
- external identifiers
-
- pmid:38536815
- scopus:85188807080
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2024.113992
- language
- English
- LU publication?
- yes
- id
- 43434df6-4b9f-45bc-90f0-54c01aa291ba
- date added to LUP
- 2024-04-15 15:33:47
- date last changed
- 2024-09-04 03:23:10
@article{43434df6-4b9f-45bc-90f0-54c01aa291ba, abstract = {{<p>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 Ca<sup>2+</sup>-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 Ca<sup>2+</sup> 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.</p>}}, author = {{Panagiotou, Styliani and Tan, Kia Wee and Nguyen, Phuoc My and Müller, Andreas and Oqua, Affiong Ika and Tomas, Alejandra and Wendt, Anna and Eliasson, Lena and Tengholm, Anders and Solimena, Michele and Idevall-Hagren, Olof}}, issn = {{2211-1247}}, keywords = {{beta cell; Ca; CP: Cell biology; CP: Metabolism; endoplasmic reticulum; insulin; membrane contact sites; OSBP; pH; phophatidylinositol 4-phosphate; secretory granule}}, language = {{eng}}, month = {{04}}, number = {{4}}, publisher = {{Cell Press}}, series = {{Cell Reports}}, title = {{OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion}}, url = {{http://dx.doi.org/10.1016/j.celrep.2024.113992}}, doi = {{10.1016/j.celrep.2024.113992}}, volume = {{43}}, year = {{2024}}, }