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Published online 11 August 2003. doi:10.1083/jcb.200211056
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© The Rockefeller University Press, 0021-9525/2003/8/683 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 683-692

Article

 Unique targeting of cytosolic phospholipase A2 to plasma membranes mediated by the NADPH oxidase in phagocytes

Zeev Shmelzer1, Nurit Haddad1, Ester Admon1, Itai Pessach1, Thomas L. Leto3, Zahit Eitan-Hazan1, Michal Hershfinkel2 and Rachel Levy1

1 Infectious Diseases Laboratory, Department of Clinical Biochemistry
2 Department of Physiology, Faculty of Health Sciences, Soroka Medical Center and Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
3 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Rachel Levy, Infectious Diseases Laboratory, Dept. of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel. Tel.: 972-8-6403186. Fax: 972-8-6467477. email: ral{at}bgumail.bgu.ac.il

Cytosolic phospholipase A2 (cPLA2)–generated arachidonic acid (AA) has been shown to be an essential requirement for the activation of NADPH oxidase, in addition to its being the major enzyme involved in the formation of eicosanoid at the nuclear membranes. The mechanism by which cPLA2 regulates NADPH oxidase activity is not known, particularly since the NADPH oxidase complex is localized in the plasma membranes of stimulated cells. The present study is the first to demonstrate that upon stimulation cPLA2 is transiently recruited to the plasma membranes by a functional NADPH oxidase in neutrophils and in granulocyte-like PLB-985 cells. Coimmunoprecipitation experiments and double labeling immunofluorescence analysis demonstrated the unique colocalization of cPLA2 and the NADPH oxidase in plasma membranes of stimulated cells, in correlation with the kinetic burst of superoxide production. A specific affinity in vitro binding was detected between GST-p47phox or GST-p67phox and cPLA2 in lysates of stimulated cells. The association between these two enzymes provides the molecular basis for AA released by cPLA2 to activate the assembled NADPH oxidase. The ability of cPLA2 to regulate two different functions in the same cells (superoxide generation and eicosanoid production) is achieved by a novel dual subcellular localization of cPLA2 to different targets.

Key Words: neutrophils; granulocyte-like PCB cells; superoxide production; arachidonic acid; PGE2

Abbreviations used in this paper: AA, arachidonic acid; cPLA2, cytosolic phospholipase A2; fMLP, formyl-methionyl-leucyl-phenylalanine; OZ, opsonized zymosan; PtdIns(4,5)P2, phosphatidylinositol 4,5-bisphosphate.


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