Ceramide 1-phosphate is required for the translocation of group IVA cytosolic phospholipase A2 and prostaglandin synthesis.

Little is known about the regulation of eicosanoid synthesis proximal to the activation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), the initial rate-limiting step. The current view is that cPLA(2)alpha associates with intracellular/phosphatidylcholine-rich membranes strictly via hydrophobic interactions in response to an increase of intracellular calcium. In opposition to this accepted mechanism of two decades, ceramide 1-phosphate (C1P) has been shown to increase the membrane association of cPLA(2)alpha in vitro via a novel site in the cationic beta-groove of the C2 domain (Stahelin, R. V., Subramanian, P., Vora, M., Cho, W., and Chalfant, C. E. (2007) J. Biol. Chem. 282, 20467-204741). In this study we demonstrate that C1P is a proximal and required bioactive lipid for the translocation of cPLA(2)alpha to intracellular membranes in response to inflammatory agonists (e.g. calcium ionophore and ATP). Last, the absolute requirement of the C1P/cPLA(2)alpha interaction was demonstrated for the production of eicosanoids using murine embryonic fibroblasts (cPLA(2)alpha(-/-)) coupled to "rescue" studies. Therefore, this study provides a paradigm shift in how cPLA(2)alpha is activated during inflammation.