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Genetic truncation of PLA2g6 leads to the impairment of endogenous store‐operated Ca2+ entry (SOCE): new molecular mechanism of STIM1 interaction with PLA2g6 and its critical role for endogenous SOCE

Ca2+‐independent phospholipase A2β (PLA2g6) is important for endogenous store‐operated Ca2+ entry (SOCE), but the molecular mechanism of its involvement is unknown. Here we report that genetic truncation of N terminus of PLA2g6 does not change its catalytic activity, but leads to a total loss of PLA2g6 activation by depletion of intracellular Ca2+ stores and ablation of PLA2g6‐ dependent SOCE in mouse embryonic fibroblasts (MEFs). Rescue experiments showed that plasma membrane‐associated (L), but not cytosolic (S) variant of PLA2g6 is required for endogenous SOCE. Co‐IP and pull‐down experiments identified N terminus of PLA2g6(L) to be critical for its molecular interaction with STIM1. Proximity ligation in situ assay revealed store depletion‐induced co‐localization of endogenous STIM1 with PLA2g6(L) in control MEFs, but not in MEFs in which N terminus of PLA2g6 was deleted. Thus, molecular interaction of STIM1 with N terminus of specific plasma membrane‐associated PLA2g6(L) presents an essential signaling step in the mechanism of endogenous SOCE activation. The loss of interaction between STIM1 and PLA2g6(L) results in impairment of endogenous SOCE and sustained depletion of intracellular Ca2+ stores.