STIM2 interacts with AMPK and regulates calcium-induced AMPK activation

AMPKis a crucial regulator of energy homeostasisthat acts downstream of its upstream kinase liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase 2 ( CaMKK2). LKB1 primarily phosphorylates AMPKafter energy stress, whereas calcium-mediated activation of AMPKrequires CaMKK2, although the regulatory mechanisms of calcium-mediated AMPKactivation remain unclear. Using biochemical, microscopic, and genetic approaches, we demonstrate that the stromal interaction molecule ( STIM)2, a calciumsensor, acts as a novel regulator of CaMKK2- AMPKsignaling. We reveal that STIM2interacts with AMPKand CaMKK2and that the increase in intracellular calciumlevels promotes AMPK colocalizationand interaction with STIM2. We further show that STIM2deficiency attenuates calcium-induced but not energy stress–induced AMPKactivation, possibly by regulating the CaMKK2- AMPKinteraction. Together, our results identify a previously unappreciated mechanism that modulates calcium-mediated AMPKactivation.—Chauhan...