SARS_virus_IRF3

SARS_virus_IRF3 - Regulation of IRF-3-dependent Innate...

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Unformatted text preview: Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus * □ S Received for publication, June 13, 2007, and in revised form, August 27, 2007 Published, JBC Papers in Press, August 30, 2007, DOI 10.1074/jbc.M704870200 Santhana G. Devaraj ‡ , Nan Wang ‡ , Zhongbin Chen § , Zihong Chen ‡ , Monica Tseng ‡ , Naina Barretto § , Rongtuan Lin ¶ , Clarence J. Peters ‡ , Chien-Te K. Tseng ‡ , Susan C. Baker § , and Kui Li ‡1 From the ‡ Department of Microbiology and Immunology and the Center of Biodefense and Emerging Infectious Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555-1019, the § Department of Microbiology and Immunology, Loyola University of Chicago, Maywood, Illinois 60153, and ¶ Lady Davis Institute for Medical Research, Montreal, Quebec H3T 1E2, Canada Severe acute respiratory syndrome coronavirus (SARS-CoV) is a novel coronavirus that causes a highly contagious respira- tory disease, SARS, with significant mortality. Although factors contributing to the highly pathogenic nature of SARS-CoV remain poorly understood, it has been reported that SARS-CoV infection does not induce type I interferons (IFNs) in cell cul- ture. However, it is uncertain whether SARS-CoV evades host detection or has evolved mechanisms to counteract innate host defenses. We show here that infection of SARS-CoV triggers a weak IFN response in cultured human lung/bronchial epithelial cells without inducing the phosphorylation of IFN-regulatory factor 3 (IRF-3), a latent cellular transcription factor that is piv- otal for type I IFN synthesis. Furthermore, SARS-CoV infection blocked the induction of IFN antiviral activity and the up-regu- lation of protein expression of a subset of IFN-stimulated genes triggered by double-stranded RNA or an unrelated paramyxovi- rus. In searching for a SARS-CoV protein capable of counteract- ing innate immunity, we identified the papain-like protease (PLpro) domain as a potent IFN antagonist. The inhibition of the IFN response does not require the protease activity of PLpro. Rather, PLpro interacts with IRF-3 and inhibits the phosphoryl- ation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid-inducible gene I/melanoma differen- tiation-associated gene 5 pathways. Our data suggest that regu- lation of IRF-3-dependent innate antiviral defenses by PLpro may contribute to the establishment of SARS-CoV infection. Upon virus infection, the host immediately launches an innate immune defense mechanism characterized by produc- tion of type I interferons (IFN 2- and - ). IFN induces the expression of hundreds of IFN-stimulated genes (ISGs) that establish an antiviral state, thereby limiting viral replication and spread (1–5). This innate antiviral response is initiated upon host detection of viral pathogen-associated molecular patterns...
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SARS_virus_IRF3 - Regulation of IRF-3-dependent Innate...

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