title: Ceramide 1-phosphate is required for the translocation of group IVA cytosolic phospholipase A2 and prostaglandin synthesis.
abstract: 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.
authors.affiliation: Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0614, USA.
authors.forename: Nadia F
authors.initials: NF
authors.lastname: Lamour
authors.forename: Preeti
authors.initials: P
authors.lastname: Subramanian
authors.forename: Dayanjan S
authors.initials: DS
authors.lastname: Wijesinghe
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stahelin
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D011247:Pregnancy; D011453:Prostaglandins / Q000096:biosynthesis*; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D014162:Transfection
chemical_list: D002518:Ceramides; D053583:Interleukin-1beta; D008164:Luminescent Proteins; D011453:Prostaglandins; C065576:ceramide 1-phosphate; D000255:Adenosine Triphosphate; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human; D002118:Calcium