Rac1 and PAK1 are upstream of IKK-ε and TBK-1 in the viral activation of interferon regulatory factor-3

The anti-viral type I interferon (IFN) response is initiated by the immediate induction of IFNbeta, which is mainly controlled by the IFN-regulatory factor-3 (IRF-3). The signaling pathways mediating viral IRF-3 activation are only poorly defined. We show that the Rho GTPase Rac1 is activated upon virus infection and controls IRF-3 phosphorylation and activity. Inhibition of Rac1 leads to reduced IFNbeta promoter activity and to enhanced virus production. As a downstream mediator of Rac signaling towards IRF-3, we have identified the kinase p21-activated kinase (PAK1). Furthermore, both Rac1 and PAK1 regulate the recently described IRF-3 activators, IkappaB kinase-V and TANK-binding kinase-1, establishing a first canonical virus-induced IRF-3 activating pathway. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.