Lsm12, an NAADP receptor, is also a PI(3,5)P2-competitive antagonist of human two pore channels

Abstract

Human two pore channels (TPCs) are endolysomal cation channels that regulate endomembrane dynamics and are involved in NAADP signaling and many pathological processes including virus infection and fat liver. TPCs are activated by two endogenous signaling molecules, NAADP and PI(3,5)P2. We recently identified Lsm12 as an NAADP receptor and a TPC regulatory protein required for NAADP-induced TPC activation and calcium mobilization from acidic organelles. In contrast to its NAADP-dependent activating effect on TPCs, we here report that Lsm12 is a PI(3,5)P2-dependent antagonist of TPCs.