A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter

Abstract

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.