Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Panagiotou, Styliani ; Tan, Kia Wee ; Nguyen, Phuoc My ; Müller, Andreas ; Oqua, Affiong Ika ; Tomas, Alejandra ; Wendt, Anna LU ; Eliasson, Lena LU orcid ; Tengholm, Anders and Solimena, Michele , et al. (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)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
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
2024-04-29 17:28:59
@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}},
}