REGULATION OF IRF-3 DEPENDENT INNATE IMMUNITY BY THE PAPAIN-LIKE PROTEASE DOMAIN OF THE SARS CORONAVIRUS
| Autor: | Devaraj, Santhana G., Wang, Nan, Chen, Zhongbin, Chen, Zihong, Tseng, Monica, Barretto, Naina, Lin, Rongtuan, Peters, Clarence J., Tseng, Chien-Te K., Baker, Susan C., Li, Kui |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
viruses
fungi virus diseases Bronchi Severe Acute Respiratory Syndrome Article Immunity Innate Cell Line Protein Structure Tertiary body regions Viral Proteins Severe acute respiratory syndrome-related coronavirus Interferon Type I Animals Humans Interferon Regulatory Factor-3 skin and connective tissue diseases Peptide Hydrolases |
| Popis: | Severe acute respiratory syndrome coronavirus (SARS-CoV) is a novel coronavirus that causes a highly contagious respiratory disease, SARS, with significant mortality. While 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 culture. 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 pivotal for type I IFN synthesis. Furthermore, SARS-CoV infection blocked the induction of IFN antiviral activity and the upregulation of protein expression of a subset of IFN-stimulated genes triggered by dsRNA or an unrelated paramyxovirus. In searching for a SARS-CoV protein capable of counteracting 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 phosphorylation 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 differentiation-associated gene 5 pathways. Our data suggest that regulation of IRF-3-dependent innate antiviral defenses by PLpro may contribute to the establishment of SARS-CoV infection. |
| Databáze: | OpenAIRE |
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