The endoplasmic reticulum-plasma membrane tethering protein TMEM24 is a regulator of cellular Ca2+ 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 dynamically localize to ER-PM contact sites and provide phosphatidylinositol, a precursor of PI(4)P and PI(4,5)P 2 , to the plasma membrane. 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 interact with the PM, and dissociates in response to both diacylglycerol and nanomolar elevations of cytosolic Ca 2+ . Release of TMEM24 into the bulk ER membrane also enables direct interactions with mitochondria, and we report that loss of TMEM24 results in excessive accumulation of Ca 2+ in both the ER and mitochondria and in impaired mitochondria function.