Structure, function, and regulation of Group V phospholipase A(2)

The hydrolysis of membrane phospholipid by phospholipase A (PLA(2)) is a ke y step in the production of inflammatory eicosanoids. Recent cell studies h ave shown that secretory group V PLA(2) (gVPLA(2)) is involved in agonist-i nduced eicosanoid biosynthesis in mouse P388D1 cell line, mast cells, and t ransfected HEI( 293 cells, gVPLA(2) is homologous to other group II PLA(2) family members but has distinctive enzymatic properties, including its acti vity to effectively hydrolyze phosphatidylcholine (PC) vesicles and the out er plasma membrane of mammalian cells. Mutational studies showed that gVPLA (2) has a unique structure that allows effective binding to PC membranes an d efficient catalysis of an active-site-bound PC substrate. Thanks to this unique structure and activity, exogenously added gVPLA(2) can induce the ei cosanoid biosynthesis in unstimulated inflammatory cells, including human n eutrophils and eosinophils, suggesting that it might be able to trigger inf lammatory responses under certain physiological conditions. Extensive struc ture-function and cell studies showed that gVPLA(2) could act directly on t he outer plasma membranes of neutrophils and eosinophils. The release of fa tty acids and lysophospholipids from the cell surfaces induces the transloc ation and activation of cytosolic PLA(2) and 5-lipoxygenase, resulting in t he leukotriene synthesis. In case of neutrophils, induction of leukotriene B-4 synthesis by gVPLA(2) leads to the phosphorylation of cytosolic PLA(2) by a leukotriene B-4 receptor and MAP kinase-mediated mechanism. Finally, h eparan sulfate proteoglycans in neutrophils appear to play a role of intern alizing and degrading the cell. surface-bound gVPLA(2) to protect the cells from extensive lipolytic damage. (C) 2000 Elsevier Science B.V, All rights reserved.