Cutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation.
TLRs signal the presence of microbial patterns and activate transcription factors. In TLR3 and TLR4, the adapter Toll-IL-1R homology domain-containing adapter molecule (TICAM-1) (also called Toll/IL-1R domain-containing adapter inducing IFN-beta (TRIF)) mediates IFN regulatory factor 3 (IRF3) phosphorylation followed by IFN-beta production. The regulatory subunit TNFR-associated factor family member-associated NF-kappaB activator (TANK) couples with the kinase complex IkappaB kinase-related kinase epsilon/NF-kappaB-activating kinase (NAK) (TANK-binding kinase 1 (TBK1)) that involveTICAM-1-dependent IFN-beta induction. There are several TANK-homologous proteins. We tested whether TICAM-1 binds and coprecipitates with TANK or its family proteins. The results are: 1) the TANK family protein NAK-associated protein 1 (NAP1), but not TANK, coprecipitates withTICAM-1; 2) NAP1 overexpression markedly enhances TBK1-mediated IFN-beta promoter activation; 3) a dominant-negative form, NAP (158-270), suppresses IRF3 activation in response to poly(I:C) or LPS; 4) RNA interference targeting of the NAP1 message results in a failure of poly(I:C)-mediated IRF3 polymerization and IFN-beta production. Thus, NAP1 is the kinase subunit responsible for TLR3/4-mediated IFN-beta induction in the TICAM-1 pathway.
Sasai
Miwa
M
Department of Immunology and Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Oshiumi
Hiroyuki
H
Matsumoto
Misako
M
Inoue
Norimitsu
N
Fujita
Fumitaka
F
Nakanishi
Makoto
M
Seya
Tsukasa
T
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3; D008562:Membrane Glycoproteins / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology*; D023062:Receptors, Interleukin-8A / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000276:immunology; D000097782:NF-kappaB-Inducing Kinase
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D008562:Membrane Glycoproteins; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D023062:Receptors, Interleukin-8A; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D000097782:NF-kappaB-Inducing Kinase; C494232:IRF3 protein, human; C484406:TANK protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human