Secretory phospholipases A2 induce neurite outgrowth in PC12 cells

sPLA(2)s (secretory phospholipases A,) belong to a broad and structurally diverse family of enzymes that hydrolyse the sn-2 ester bond of glycerophospholipids. We previously showed that a secreted fungal 15 kDa protein, named p 15, as well as its orthologue from Streptomyces coelicolor (named Scp 15) induce neurite outgrowth in PC 12 cells at nanomolar concentrations. We report here that both p15 and Scp15 are members of a newly identified group of fungal/bacterial sPLAs. The phospholipid-hydrolysing activity of p 15 is absolutely required for neurite outgrowth induction. Mutants with a reduced PLA(2) activity exhibited a comparable reduction in neurite-inducing activity, and the ability to induce neurites closely matched the capacity of various p 15 forms to promote fatty acid release from live PC12 cells. A structurally divergent member of the sPLA, family, bee venom sPLA2, also induced neurites, in a phospholipase activity-dependent manner, and the same effect was elicited by mouse group V and X sPLA(2)S, but not by group IB and IIA sPLA2s. Lysophosphatidylcholine, but not other lysophospholipids, nor arachidonic acid, elicited neurite outgrowth in an L-type Ca2+ channel activity-dependent manner. In addition, p15-induced neuritogenesis was unaffected by various inhibitors that block arachidonic acid conversion into bioactive eicosanoids. Altogether, these results delineate a novel, Ca2+ and lysophosphatidylcholine-dependent neurotrophin-like role of sPLA(2)S in the nervous system.