Role of the Rho GTPase Rac in the activation of the phagocyte NADPH oxidase: outsourcing a key task

Small GTPases. 2014;5:e27952. doi: 10.4161/sgtp.27952. Epub 2014 Mar 5.

Abstract

The superoxide-generating NADPH oxidase of phagocytes consists of the membrane-associated cytochrome b 558 (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; p67phox; superoxide.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cell Membrane / metabolism
  • Cytochrome b Group / chemistry
  • Cytochrome b Group / metabolism
  • Humans
  • Membrane Glycoproteins / metabolism
  • NADPH Oxidase 2
  • NADPH Oxidases / chemistry
  • NADPH Oxidases / metabolism*
  • Phagocytes / cytology
  • Phagocytes / enzymology
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Reactive Oxygen Species / metabolism
  • rac GTP-Binding Proteins / chemistry
  • rac GTP-Binding Proteins / metabolism*

Substances

  • Cytochrome b Group
  • Membrane Glycoproteins
  • Phosphoproteins
  • Reactive Oxygen Species
  • neutrophil cytosol factor 67K
  • cytochrome b558
  • CYBB protein, human
  • NADPH Oxidase 2
  • NADPH Oxidases
  • rac GTP-Binding Proteins