期刊
BLOOD
卷 116, 期 23, 页码 4978-4989出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-03-275602
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资金
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Medical Research Council (MRC) [G0600840]
- Wellcome Trust [WT085889MA]
- UCB BBSRC
- BBSRC [BBS/E/B/0000C218, BBS/E/B/0000M211] Funding Source: UKRI
- MRC [G0600840, MC_U117527252, G9805886] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C218, BBS/E/B/0000M211] Funding Source: researchfish
- Medical Research Council [G9805886, G0600840, MC_U117527252] Funding Source: researchfish
The generation of reactive oxygen species (ROS) by the nicotinamide adenine dinucleotide phosphate oxidase is an important mechanism by which neutrophils kill pathogens. The oxidase is composed of a membrane-bound cytochrome and 4 soluble proteins (p67(phox), p40(phox), p47(phox), and GTP-Rac). These components form an active complex at the correct time and subcellular location through a series of incompletely understood mutual interactions, regulated, in part, by GTP/GDP exchange on Rac, protein phosphorylation, and binding to lipid messengers. We have used a variety of assays to follow the spatiotemporal assembly of the oxidase in genetically engineered primary mouse neutrophils, during phagocytosis of both serum- and immunoglobulin G-opsonized targets. The oxidase assembles directly on serum- Staphylococcus aureus-containing phagosomes within seconds of phagosome formation; this process is only partially dependent (similar to 30%) on PtdIns3P binding to p40(phox,) but totally dependent on Rac1/2 binding to p67(phox). In contrast, in response to immunoglobulin G-targets, the oxidase first assembles on a tubulovesicular compartment that develops at sites of granule fusion to the base of the emerging phagosome; oxidase assembly and activation is highly dependent on both PtdIns3P-p40(phox) and Rac2-p67(phox) interactions and delivery to the phagosome is regulated by Rab27a. These results define a novel pathway for oxidase assembly downstream of FcR-activation. (Blood. 2010;116(23):4978-4989)
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