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Molecular and Cellular Biology, March 2006, p. 2160-2174, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2160-2174.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Involvement of Rac1 in Activation of Multicomponent Nox1- and Nox3-Based NADPH Oxidases

Takehiko Ueyama,1* Miklós Geiszt,2 and Thomas L. Leto1*

The Molecular Defenses Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Department of Physiology, Semmelweis University, Faculty of Medicine, P.O. Box 259, H-1444 Budapest, Hungary2

Received 17 June 2005/ Returned for modification 14 July 2005/ Accepted 30 December 2005

Several Nox family NADPH oxidases function as multicomponent enzyme systems. We explored determinants of assembly of the multicomponent oxidases Nox1 and Nox3 and examined the involvement of Rac1 in their regulation. Both enzymes are supported by p47phox and p67phox or homologous regulators called Noxo1 and Noxa1, although Nox3 is less dependent on these cofactors for activity. Plasma membrane targeting of Noxa1 depends on Noxo1, through tail-to-tail interactions between these proteins. Noxa1 can support Nox1 without Noxo1, when targeted to the plasma membrane by fusing membrane-binding sequences from Rac1 (amino acids 183 to 192) to the C terminus of Noxa1. However, membrane targeting of Noxa1 is not sufficient for activation of Nox1. Both the Noxo1-independent and -dependent Nox1 systems involve Rac1, since they are affected by Rac1 mutants or Noxa1 mutants defective in Rac binding or short interfering RNA-mediated Rac1 silencing. Nox1 or Nox3 expression promotes p22phox transport to the plasma membrane, and both oxidases are inhibited by mutations in the p22phox binding sites (SH3 domains) of the Nox organizers (p47phox or Noxo1). Regulation of Nox3 by Rac1 was also evident from the effects of mutant Rac1 or mutant Nox3 activators (p67phox or Noxa1) or Rac1 silencing. In the absence of Nox organizers, the Nox activators (p67phox or Noxa1) colocalize with Rac1 within ruffling membranes, independently of their ability to bind Rac1. Thus, Rac1 regulates both oxidases through the Nox activators, although it does not appear to direct the subcellular localization of these activators.

* Corresponding author. Mailing address for Thomas L. Leto: NIH, NIAID, Twinbrook II, Room 203, 12441 Parklawn Dr., Bethesda, MD 20892. Phone: (301) 402-5120. Fax: (301) 480-1731. E-mail: tleto{at}nih.gov. Mailing address for Takehiko Ueyama: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, 1-1, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan. Phone: 81-78-803-5962. Fax: 81-78-803-5971. E-mail: tueyama{at}kobe-u.ac.jp.

Molecular and Cellular Biology, March 2006, p. 2160-2174, Vol. 26, No. 6
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.6.2160-2174.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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