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

• Published in: Science (American Association for the Advancement of Science) Vol. 355; no. 6326; p. 709
• Main Authors: Lees, Joshua A., Messa, Mirko, Sun, Elizabeth Wen, Wheeler, Heather, Torta, Federico, Wenk, Markus R., De Camilli, Pietro, Reinisch, Karin M.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 17.02.2017; The American Association for the Advancement of Science; AAAS
• Subjects: Animals; BASIC BIOLOGICAL SCIENCES; Beta cells; Biological Transport; Bursts; Calcium; Calcium (intracellular); Calcium channels; Calcium influx; Calcium ions; Calcium Signaling; Calcium signalling; Cell Membrane - metabolism; Cercopithecus aethiops; Contact; COS Cells; Dephosphorylation; Diabetes; Diabetes mellitus; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Exocytosis; Gene Knockout Techniques; Glucose; Granular materials; HeLa Cells; Humans; Hydrolysis; Insulin; Insulin - metabolism; Insulin Secretion; Ion channels; Lipid Metabolism; Lipid-binding protein; Lipids; Localization; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mitochondria; Modules; Oscillations; Patients; Phosphatidylinositol 4,5-diphosphate; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phospholipase C; Phosphorylation; Plasma; Pools; Precursors; Protein transport; Proteins; Replenishment; RESEARCH ARTICLE SUMMARY; Secretion; Secretions; Signal transduction; Signaling; Stimulation; Synaptotagmin; Transport
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aah6171

Insulin release takes place in two phases: a first rapid burst followed by a series of small exocytic bursts that coincide with pulsatile spikes in cytosolic Ca 2+ levels. The second phase is impaired in patients with type II diabetes, underscoring the importance of understanding its molecular basis. Lees et al. report a mechanism through which TMEM24, a lipid transport protein that concentrates at endoplasmic reticulum–plasma membrane contact sites, regulates the pulsatility of cytosolic Ca 2+ and phosphoinositide signaling. This process in turn regulates pulsatile insulin secretion during the slow insulin release phase. Science , this issue p. eaah6171 Direct lipid transport between the endoplasmic reticulum and the plasma membrane helps to control insulin secretion. 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)P 2 ] precursor phosphatidylinositol between bilayers, allowing replenishment of PI(4,5)P 2 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.