Studies on ghe novel neurotrophic factor, secretory phospholiase A_2

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Secretory phospholipases A_2(sPLA_<2s> 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 15kDa protein, named p15, as well as its ortholog from Streptomyces coelicolor (named Scp15) induce neurite outgrowth in PC12 cells at nanomolar concentrations. We report here that both p15 and Scp15 are members of a newly identified group of fungal/bacterial sPLA_<2s>. The phospholipids hydrolyzing activity of p15 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 neuritis closely matched the capacity of various p15 forms to promote fatty acid release from livePC12 cells. A structurally divergent member of the sPLA_2 family, bee venom sPLA_2, also induced neuritis in a phospholipase activity-dependent manner, and the same effect was elicited by mouse group V and X sPLA_<2s>, but not by group IB and IIAsPLA_<2s>. Lysophosphatidylcholine, but not other lysophospholipids, nor arachidonic acid, elicited neurite outgrowth in an L-type Ca^<2+> 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, Ca^<2+>-and lysophosphatidylcholine-dependent neurotrophin-like role of sPLA_<2s> in the nervous system.