Role of Rac GTPase activating proteins in regulation of NADPH oxidase in human neutrophils

Ákos M. Lorincz, Gábor Szarvas, Susan M.E. Smith, Erzsébet Ligeti

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Precise spatiotemporal regulation of O2--generating NADPH oxidases (Nox) is a vital requirement. In the case of Nox1-3, which depend on the small GTPase Rac, acceleration of GTP hydrolysis by GTPase activating protein (GAP) could represent a feasible temporal control mechanism. Our goal was to investigate the molecular interactions between RacGAPs and phagocytic Nox2 in neutrophilic granulocytes. In structural studies we revealed that simultaneous interaction of Rac with its effector protein p67phox and regulatory protein RacGAP was sterically possible. The effect of RacGAPs was experimentally investigated in a cell-free O2--generating system consisting of isolated membranes and recombinant p47phox and p67phox proteins. Addition of soluble RacGAPs decreased O 2- production and there was no difference in the effect of four RacGAPs previously identified in neutrophils. Depletion of membrane-associated RacGAPs had a selective effect: a decrease in ARHGAP1 or ARHGAP25 level increased O2- production but a depletion of ARHGAP35 had no effect. Only membrane-localized RacGAPs seem to be able to interact with Rac when it is assembled in the Nox2 complex. Thus, in neutrophils multiple RacGAPs are involved in the control of O2- production by Nox2, allowing selective regulation via different signaling pathways.

Original languageEnglish
Pages (from-to)65-71
Number of pages7
JournalFree Radical Biology and Medicine
Volume68
DOIs
Publication statusPublished - Mar 1 2014

Keywords

  • GTPase activating protein (GAP)
  • Molecular modeling
  • NADPH oxidase
  • Rac small GTPase
  • Superoxide production

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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