The endoplasmic reticulum–plasma membrane tethering protein TMEM24 is a regulator of cellular Ca(2+) homeostasis

Endoplasmic reticulum (ER)–plasma membrane (PM) contacts are sites of lipid exchange and Ca(2+) transport, and both lipid transport proteins and Ca(2+) channels specifically accumulate at these locations. In pancreatic β-cells, both lipid and Ca(2+) signaling are essential for insulin secretion. The recently characterized lipid transfer protein TMEM24 (also known as C2CD2L) dynamically localizes to ER–PM contact sites and provides phosphatidylinositol, a precursor of phosphatidylinositol-4-phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], to the PM. β-cells lacking TMEM24 exhibit markedly suppressed glucose-induced Ca(2+) oscillations and insulin secretion, but the underlying mechanism is not known. We now show that TMEM24 only weakly interacts with the PM, and dissociates in response to both diacylglycerol and nanomolar elevations of cytosolic Ca(2+). Loss of TMEM24 results in hyper-accumulation of Ca(2+) in the ER and in excess Ca(2+) entry into mitochondria, with resulting impairment in glucose-stimulated ATP production.