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Negative regulation of the retinoic acid-inducible gene I- induced antiviral state by the ubiquitin-editing protein A20.
Activation of the interferon regulatory factors (IRFs) 3 and 7 transcription factors is essential for the induction of type I interferon ( IFN) and development of the innate antiviral response. Retinoic acid-inducible gene I has been shown to contribute to virus- induced IFN production independent of the Toll-like receptor pathways in response to a variety of RNA viruses and double-stranded RNA. In the present study, we demonstrate that the NF-kappaB-inducible, anti-apoptotic protein A20 efficiently blocks RIG-I-mediated activation of NF-kappaB-, IRF-3-, and IRF-7-dependent promoters but only weakly interferes with TRIF-TLR-3- mediated IFN activation. Expression of A20 completely blocked CARD domain containing DeltaRIG-I- induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding. The level of A20 inhibition was upstream of the TBK1/IKKepsilon kinases that phosphorylate IRF3 and IRF7 and paradoxically, A20 selectively degraded the TRIF protein but not RIG-I. A20 possesses two ubiquitin-editing domains, an N-terminal deubiquitination domain and a C-terminal ubiquitin ligase domain consisting of seven zinc finger domains. Deletion of the N-terminal de-ubiquitination domain had no significant effect on the inhibitory effect of A20, whereas deletion or mutation of zinc finger motif 7 ablated the inhibitory function of A20 on IRF- or NF-kappaB-mediated gene expression. Furthermore, cells stably expressing the active form of RIG-I induced an antiviral state that interfered with replication of vesicular stomatitis virus, an effect that was reversed by stable co-expression of A20. These results suggest that the virus-inducible, NF-kappaB-dependent activation of A20 functions as a negative regulator of RIG-I-mediated induction of the antiviral state.[1]References
- Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. Lin, R., Yang, L., Nakhaei, P., Sun, Q., Sharif-Askari, E., Julkunen, I., Hiscott, J. J. Biol. Chem. (2006) [Pubmed]
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