Rac1 and PAK1 are upstream of IKK-epsilon 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 IFN beta, 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 IFN beta 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, I kappa B kinase- and TANK-binding kinase-1, establishing a first canonical virus-induced IRF-3 activating pathway.
Ehrhardt
Christina
C
Institute of Molecular Medicine, Heinrich-Heine-Universität, Universitätsstrasse 1, D-40225, Duesseldorf, Germany. christina.bhrhardt@uni-duesseldorf.de
Kardinal
Christian
C
Wurzer
Walter J
WJ
Wolff
Thorsten
T
von Eichel-Streiber
Christoph
C
Pleschka
Stephan
S
Planz
Oliver
O
Ludwig
Stephan
S
D000818:Animals; D050882:CREB-Binding Protein; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004285:Dogs; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D009980:Influenza A virus / Q000472:pathogenicity; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014779:Virus Replication; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D009687:Nuclear Proteins; D012330:RNA, Double-Stranded; D015534:Trans-Activators; D014157:Transcription Factors; D016899:Interferon-beta; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D054462:p21-Activated Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020830:rac1 GTP-Binding Protein