A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter.
Toll-like receptor 3 (TLR3) recognizes dsRNA generated during viral infection and activation of TLR3 results in induction of type I interferons (IFNs) and cellular anti-viral response. TLR3 is associated with a TIR domain-containing adapter protein TRIF, which activates distinct downstream pathways leading to activation of NF-kappaB and ISRE sites in the promoters of type I IFNs. We show here that A20, a NF-kappaB-inducible zinc finger protein that has been demonstrated to be an inhibitor of TNF-induced NF-kappaB activation and a physiological suppressor of inflammatory response, potently inhibited TLR3- and Sendai virus-mediated activation of ISRE and NF-kappaB and IFN-beta promoter in reporter gene assays. A20 also inhibited TRIF-, but not its downstream signaling components TBK1-, IKKbeta-, and IKKepsilon-mediated activation of ISRE and NF-kappaB and IFN-beta promoter. Moreover, A20 interacted with TRIF in co-immunoprecipitation experiments. Finally, expression of A20 could be induced at protein level by Sendai virus infection. These data suggest that A20 targets TRIF to inhibit TLR3-mediated induction of IFN-beta transcription and functions as a feedback negative regulator for TLR3 signaling and cellular anti-viral response.
Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, China.
Yan-Yi
YY
Wang
Lianyun
L
Li
Ke-Jun
KJ
Han
Zhonghe
Z
Zhai
Hong-Bing
HB
Shu
D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors; D015153:Blotting, Western; D002460:Cell Line; D004268:DNA-Binding Proteins; D017930:Genes, Reporter; D006801:Humans; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D011971:Receptors, Immunologic / Q000378:metabolism; D020218:Response Elements; D029082:Sendai virus / Q000502:physiology; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014775:Virus Activation
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D016899:Interferon-beta; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3