The p40  and p47  PX Domains of NADPH Oxidase Target Cell Membranes via Direct and Indirect Recruitment by Phosphoinositides

Zhan, Yong; Virbasius, Joseph V.; Song, Xi; Pomerleau, Darcy P.; Zhou, G.T.

doi:10.1074/jbc.m109520200

Cited by 105 publications

(115 citation statements)

References 42 publications

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“…generation in cell-free assays (42)(43)(44) and in K562 cells (45). The PX domain of p40 phox is considered important in the interaction with the lipid products of PI3Ks (44,46,47), which may be one of the mechanisms for the potentiation of O 2 . production.…”

Section: Discussionmentioning

confidence: 99%

Reconstitution of Chemotactic Peptide-Induced Nicotinamide Adenine Dinucleotide Phosphate (Reduced) Oxidase Activation in Transgenic COS-phox Cells

Nanamori

Sang

et al. 2004

The Journal of Immunology

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A whole-cell-based reconstitution system was developed to study the signaling mechanisms underlying chemoattractant-induced activation of NADPH oxidase. This system takes advantage of the lack of formyl peptide receptor-mediated response in COS-phox cells expressing gp91phox, p22phox, p67phox, and p47phox, which respond to phorbol ester and arachidonic acid with O⨪2 production. By exogenous expression of signaling molecules enriched in neutrophils, we have identified several critical components for fMLP-induced NADPH oxidase activation. Expression of PKCδ, but not PKCα, -βII, and -ζ, is necessary for the COS-phox cells to respond to fMLP. A role of PKCδ in neutrophil NADPH oxidase was confirmed based on the ability of fMLP to induce PKCδ translocation and the sensitivity of fMLP-induced O⨪2 production to rottlerin, a PKCδ-selective inhibitor. Optimal reconstitution also requires phospholipase C-β2 and PI3K-γ. We found that formyl peptide receptor could use the endogenous Rac1 as well as exogenous Rac1 and Rac2 for NADPH oxidase activation. Exogenous expression of p40phox potentiated fMLP-induced O⨪2 production and raised the level of O⨪2 in unstimulated cells. Collectively, these results provide first direct evidence for reconstituting fMLP-induced O⨪2 production in a nonhemopoietic cell line, and demonstrate the requirement of multiple signaling components for optimal activation of NADPH oxidase by a chemoattractant.

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Section: Discussionmentioning

confidence: 99%

Reconstitution of Chemotactic Peptide-Induced Nicotinamide Adenine Dinucleotide Phosphate (Reduced) Oxidase Activation in Transgenic COS-phox Cells

Nanamori

Sang

et al. 2004

The Journal of Immunology

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“…It is known that p47 phox but not p67 phox contains a Phox homology domain. The Phox homology domain of P47 phox binds phosphatidylinositol 3-phosphate, and such lipid modification of the protein triggers its attachment to the plasma membrane (39). Thus, it is logical that in adherent cells, the translocation of p47 phox but not that of p67 phox to the membrane does require PI 3-kinase activity.…”

Section: Ligation Of ␤ 2 Integrins Induces Translocation Of Rac1 But mentioning

confidence: 99%

Down-regulation of Rac Activity during β2 Integrin-mediated Adhesion of Human Neutrophils

Dib

Melander

Axelsson

et al. 2003

Journal of Biological Chemistry

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In human neutrophils, ␤ 2 integrin engagement mediated a decrease in GTP-bound Rac1 and Rac2. Pretreatment of neutrophils with LY294002 or PP1 (inhibiting phosphatidylinositol 3-kinase (PI 3-kinase) and Src kinases, respectively) partly reversed the ␤ 2 integrin-induced down-regulation of Rac activities. In contrast, ␤ 2 integrins induced stimulation of Cdc42 that was independent of Src family members. The PI 3-kinase dependence of the ␤ 2 integrin-mediated decrease in GTP-bound Rac could be explained by an enhanced Rac-GAP activity, since this activity was blocked by LY204002, whereas PP1 only had a minor effect. The fact that only Rac1 but not Rac2 (the dominating Rac) redistributed to the detergent-insoluble fraction and that it was independent of GTP loading excludes the possibility that down-regulation of Rac activities was due to depletion of GTPbound Rac from the detergent-soluble fraction. The ␤ 2 integrin-triggered relocalization of Rac1 to the cytoskeleton was enabled by a PI 3-kinase-induced dissociation of Rac1 from LyGDI. The dissociations of Rac1 and Rac2 from LyGDI also explained the PI 3-kinase-dependent translocations of Rac GTPases to the plasma membrane. However, these accumulations of Rac in the membrane, as well as that of p47 phox and p67 phox , were also regulated by Src tyrosine kinases. Inasmuch as Rac GTPases are part of the NADPH oxidase and the respiratory burst is elicited in neutrophils adherent by ␤ 2 integrins, our results indicate that activation of the NADPH oxidase does not depend on the levels of Rac-GTP but instead requires a ␤ 2 integrin-induced targeting of the Rac GTPases as well as p47 phox and p67 phox to the plasma membrane.

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“…The same lipid binding site mutation also decreases the ability of NOXO1 to support Nox1-dependent ROS generation, consistent with an effect on localization. An analogous mutation in the lipid binding site in p47 phox failed to interfere with binding to the plasma membrane (29), indicating that for p47 phox , association with other biomolecules (such as p22 phox ) may provide significant binding energy that cooperates with lipid binding in localizing p47…”

Section: Figmentioning

confidence: 99%

“…The PX domain of p47 phox contains a proline-rich sequence that appears to participate in intradomain binding to the C-SH3 domain of p47 phox (22,26). Moreover, PX domains function as binding sites for phosphatidylinositol phosphates (25,27,29,40). The internal interactions within p47 phox mask the binding to lipids, preventing membrane association.…”

Section: Figmentioning

confidence: 99%

“…The latter, in addition to forming a heterodimer with gp91 phox (23,24), provides a proline-rich binding site for the p47 phox bis-SH3 domain. p47 phox also contains a lipid binding domain (the PX domain) with specificity for 3-phosphorylated lipids, the products of phosphatidylinositol 3-kinase (25)(26)(27)(28)(29). The latter is activated in cells exposed to bacterial products or immune mediators, as are the kinases that phosphorylate p47 phox itself.…”

mentioning

confidence: 99%

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NOXO1, Regulation of Lipid Binding, Localization, and Activation of Nox1 by the Phox Homology (PX) Domain

Cheng

Lambeth

2004

Journal of Biological Chemistry

187

186

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The p40 and p47 PX Domains of NADPH Oxidase Target Cell Membranes via Direct and Indirect Recruitment by Phosphoinositides

Cited by 105 publications

References 42 publications

Reconstitution of Chemotactic Peptide-Induced Nicotinamide Adenine Dinucleotide Phosphate (Reduced) Oxidase Activation in Transgenic COS-phox Cells

Reconstitution of Chemotactic Peptide-Induced Nicotinamide Adenine Dinucleotide Phosphate (Reduced) Oxidase Activation in Transgenic COS-phox Cells

Down-regulation of Rac Activity during β2 Integrin-mediated Adhesion of Human Neutrophils

NOXO1, Regulation of Lipid Binding, Localization, and Activation of Nox1 by the Phox Homology (PX) Domain

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