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Science. 2017 Feb 17;355(6326). pii: eaah6171. doi: 10.1126/science.aah6171.

Lipid transport by TMEM24 at ER-plasma membrane contacts regulates pulsatile insulin secretion.

Lees JA1, Messa M1,2,3,4, Sun EW1,2,3,4, Wheeler H1,2,3,4, Torta F5, Wenk MR5, De Camilli P6,2,3,4,7, Reinisch KM6.

Author information

1
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
4
Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
5
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore.
6
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. pietro.decamilli@yale.edu karin.reinisch@yale.edu.
7
Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.

Abstract

Insulin is released by β cells in pulses regulated by calcium and phosphoinositide signaling. Here, we describe how transmembrane protein 24 (TMEM24) helps coordinate these signaling events. We showed that TMEM24 is an endoplasmic reticulum (ER)-anchored membrane protein whose reversible localization to ER-plasma membrane (PM) contacts is governed by phosphorylation and dephosphorylation in response to oscillations in cytosolic calcium. A lipid-binding module in TMEM24 transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol between bilayers, allowing replenishment of PI(4,5)P2 hydrolyzed during signaling. In the absence of TMEM24, calcium oscillations are abolished, leading to a defect in triggered insulin release. Our findings implicate direct lipid transport between the ER and the PM in the control of insulin secretion, a process impaired in patients with type II diabetes.

PMID:
28209843
PMCID:
PMC5414417
DOI:
10.1126/science.aah6171
[Indexed for MEDLINE]
Free PMC Article

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