Role of the Rho GTPase Rac in the activation of the phagocyte NADPH oxidase

Abstract

The superoxide-generating NADPH oxidase of phagocytes consists of the membrane-associated cytochrome b₅₅₈ (a heterodimer of Nox2 and p22^phox) and 4 cytosolic components: p47^phox, p67^phox, p40^phox, and the small GTPase, Rac, in complex with RhoGDI. Superoxide is produced by the NADPH-driven reduction of molecular oxygen, via a redox gradient located in Nox2. Electron flow in Nox2 is initiated by interaction with cytosolic components, which translocate to the membrane, p67^phox playing the central role. The participation of Rac is expressed in the following sequence: (1) Translocation of the RacGDP-RhoGDI complex to the membrane; (2) Dissociation of RacGDP from RhoGDI; (3) GDP to GTP exchange on Rac, mediated by a guanine nucleotide exchange factor; (4) Binding of RacGTP to p67^phox; (5) Induction of a conformational change in p67^phox, promoting interaction with Nox2. The particular involvement of Rac in NADPH oxidase assembly serves as a paradigm for signaling by Rho GTPases, in general.

Keywords: :

• GEF
• NADPH oxidase
• Rac1
• Rac2
• Rho GTPases
• RhoGDI
• cell-free system
• cytochrome b₅₅₈
• p67^phox
• superoxide

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Our own research described in this report was supported by the Julius Friedrich Cohnheim-Minerva Center for Phagocyte Research, the Ela Kodesz Institute of Host Defense against Infectious Diseases, Israel Science Foundation Grants 428/01, 19/05, 49/09, and 300/13, the Roberts-Guthman Chair in Immunopharmacology, the Walter J. Levy Benevolent Trust, the Roberts Fund, the Milken–Lowell Fund, the Wallis Foundation, the Rubanenko Fund, and the Joseph and Shulamit Salomon Fund.