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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3867-3877. Prepublished online as a Blood First Edition Paper on August 18, 2008; DOI 10.1182/blood-2007-11-126029. This Article Full Text (PDF) Supplemental Figures and Videos All Versions of this Article: blood-2007-11-126029v1 112/9/3867    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tian, W. Articles by Dinauer, M. C. Search for Related Content PubMed PubMed Citation Articles by Tian, W. Articles by Dinauer, M. C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 26, 2007 Accepted July 12, 2008 FcR-stimulated activation of the NADPH oxidase: Phosphoinositide binding protein p40phox regulates NADPH oxidase activity after enzyme assembly on the phagosome Wei Tian, Xing Jun Li, Natalie D. Stull, Wenyu Ming, Chang-Il Suh, Sarah A. Bissonnette, Michael B. Yaffe, Sergio Grinstein, Simon J. Atkinson, and Mary C. Dinauer* Herman B Wells Center for Pediatric Research, Department of Pediatrics (Hematology/Oncology), Indiana University School of Medicine, Indianapolis, IN, United States Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States Division of Biological Engineering, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States Division of Cell Biology, Hospital for Sick Children, Toronto, Canada Department of Medicine (Nephrology), Indiana University School of Medicine, Indianapolis, IN, United States Departments of Microbiology/Immunology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States * Corresponding author; email: mdinauer{at}iupui.edu. The 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 FcR-induced oxidase activation, we used immunofluorescence and real time imaging of FcR-induced phagocytosis. YFP-tagged p67phox and p40phox translocated to granulocyte phagosomes prior to 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 FcR-induced NADPH oxidase activity rather than assembly, and stimulates superoxide production via a PI3P signal that increases after phagosome internalization. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. D. Matute, A. A. Arias, N. A. M. Wright, I. Wrobel, C. C. M. Waterhouse, X. J. Li, C. C. Marchal, N. D. Stull, D. B. Lewis, M. Steele, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity Blood, October 8, 2009; 114(15): 3309 - 3315. [Abstract] [Full Text] [PDF] D. Gianni, B. Diaz, N. Taulet, B. Fowler, S. A. Courtneidge, and G. M. Bokoch Novel p47phox-Related Organizers Regulate Localized NADPH Oxidase 1 (Nox1) Activity Sci. Signal., September 15, 2009; 2(88): ra54 - ra54. [Abstract] [Full Text] [PDF] J. Huang, V. Canadien, G. Y. Lam, B. E. Steinberg, M. C. Dinauer, M. A. O. Magalhaes, M. Glogauer, S. Grinstein, and J. H. Brumell Activation of antibacterial autophagy by NADPH oxidases PNAS, April 14, 2009; 106(15): 6226 - 6231. [Abstract] [Full Text] [PDF] X. J. Li, W. Tian, N. D. Stull, S. Grinstein, S. Atkinson, and M. C. Dinauer A Fluorescently Tagged C-Terminal Fragment of p47phox Detects NADPH Oxidase Dynamics during Phagocytosis Mol. Biol. Cell, March 1, 2009; 20(5): 1520 - 1532. [Abstract] [Full Text] [PDF] A. D. Kennedy and F. R. DeLeo PI3K and NADPH oxidase: a class act Blood, December 15, 2008; 112(13): 4788 - 4789. [Full Text] [PDF]

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