FcγR-stimulated activation of the NADPH oxidase: phosphoinositide-binding protein p40phox regulates NADPH oxidase activity after enzyme assembly on the phagosome

Author:

Tian Wei1,Li Xing Jun1,Stull Natalie D.1,Ming Wenyu1,Suh Chang-Il1,Bissonnette Sarah A.2,Yaffe Michael B.234,Grinstein Sergio5,Atkinson Simon J.6,Dinauer Mary C.17

Affiliation:

1. Herman B Wells Center for Pediatric Research, Department of Pediatrics (Hematology/Oncology), Riley Hospital for Children, Indiana University School of Medicine, Indianapolis;

2. Department of Biology and

3. Division of Biological Engineering, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge;

4. Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA;

5. Division of Cell Biology, Hospital for Sick Children, Toronto, ON; and

6. Departments ofMedicine (Nephrology) and

7. Microbiology/Immunology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis

Abstract

AbstractThe phagocyte NADPH oxidase generates superoxide for microbial killing, and includes a membrane-bound flavocytochrome b558 and cytosolic p67phox, p47phox, and p40phox subunits that undergo membrane translocation upon cellular activation. The function of p40phox, which binds p67phox in resting cells, is incompletely understood. Recent studies showed that phagocytosis-induced superoxide production is stimulated by p40phox and its binding to phosphatidylinositol-3-phosphate (PI3P), a phosphoinositide enriched in membranes of internalized phagosomes. To better define the role of p40phox in FcγR-induced oxidase activation, we used immunofluorescence and real-time imaging of FcγR-induced phagocytosis. YFP-tagged p67phox and p40phox translocated to granulocyte phagosomes before phagosome internalization and accumulation of a probe for PI3P. p67phox and p47phox accumulation on nascent and internalized phagosomes did not require p40phox or PI3 kinase activity, although superoxide production before and after phagosome sealing was decreased by mutation of the p40phox PI3P-binding domain or wortmannin. Translocation of p40phox to nascent phagosomes required binding to p67phox but not PI3P, although the loss of PI3P binding reduced p40phox retention after phagosome internalization. We conclude that p40phox functions primarily to regulate FcγR-induced NADPH oxidase activity rather than assembly, and stimulates superoxide production via a PI3P signal that increases after phagosome internalization.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference58 articles.

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