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J. Biol. Chem., Vol. 281, Issue 4, 2095-2103, January 27, 2006

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Negative Regulation of the Retinoic Acid-inducible Gene I-induced Antiviral State by the Ubiquitin-editing Protein A20^*

Rongtuan Lin1, Long Yang¶, Peyman Nakhaei¶, Qiang Sun, Ehssan Sharif-Askari2, Ilkka Julkunen||, and John Hiscott¶3

From the Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, and Departments of ^¶Microbiology & Immunology and Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada and the ^||National Public Health Institute and University of Helsinki, Helsinki FIN-00300, Finland

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-B-inducible, anti-apoptotic protein A20 efficiently blocks RIG-I-mediated activation of NF-B-, 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 RIG-I-induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding. The level of A20 inhibition was upstream of the TBK1/IKK 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-B-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-B-dependent activation of A20 functions as a negative regulator of RIG-I-mediated induction of the antiviral state.

Received for publication, September 20, 2005 , and in revised form, November 14, 2005.

^* This work was supported in part by grants from the Cancer Research Society Inc. (to R. L.), Canadian Institutes of Health Research (to R. L. and J. H.), the Canadian Network for Vaccines and Immunotherapeutics (to J. H.), and by the National Cancer Institute of Canada, with the support of the Canadian Cancer Society (to J. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2.

² Supported by a Post-doctoral Fellowship from the Fonds de la Recherche en Santé du Quebec.

³ Supported by a Canadian Institutes for Health Research Senior Investigator award.

¹ Supported by the Fonds de la Recherche en Santé du Quebec Chercheur-boursier: To whom correspondence should be addressed: Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine, Montreal, Quebec H3T 1E2, Canada. Tel.: 514–340-8222 (ext. 5272); Fax: 514–340-7576; E-mail: rongtuan.lin{at}mcgill.ca.

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