Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus

Santhana G. Devaraj, Nan Wang, Zhongbin Chen, Zihong Chen, Monica Tseng, Naina Barretto, Rongtuan Lin, Clarence J. Peters, Chien-Te Tseng, Susan C. Baker, Kui Li

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a novel coronavirus that causes a highly contagious respiratory 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 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 up-regulation of protein expression of a subset of IFN-stimulated genes triggered by double-stranded RNA 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.

Original languageEnglish (US)
Pages (from-to)32208-32221
Number of pages14
JournalJournal of Biological Chemistry
Volume282
Issue number44
DOIs
StatePublished - Nov 2 2007

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Interferon Regulatory Factor-3
Severe Acute Respiratory Syndrome
Coronavirus
Papain
Innate Immunity
Interferons
Peptide Hydrolases
Interferon Type I
Coronavirus Infections
Phosphorylation
Genes
Antiviral Agents
Toll-Like Receptor 3
Pulmonary diseases
Double-Stranded RNA
Tretinoin
Cell culture
Proteins
Transcription Factors
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. / Devaraj, Santhana G.; Wang, Nan; Chen, Zhongbin; Chen, Zihong; Tseng, Monica; Barretto, Naina; Lin, Rongtuan; Peters, Clarence J.; Tseng, Chien-Te; Baker, Susan C.; Li, Kui.

In: Journal of Biological Chemistry, Vol. 282, No. 44, 02.11.2007, p. 32208-32221.

Research output: Contribution to journalArticle

Devaraj, SG, Wang, N, Chen, Z, Chen, Z, Tseng, M, Barretto, N, Lin, R, Peters, CJ, Tseng, C-T, Baker, SC & Li, K 2007, 'Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus', Journal of Biological Chemistry, vol. 282, no. 44, pp. 32208-32221. https://doi.org/10.1074/jbc.M704870200
Devaraj, Santhana G. ; Wang, Nan ; Chen, Zhongbin ; Chen, Zihong ; Tseng, Monica ; Barretto, Naina ; Lin, Rongtuan ; Peters, Clarence J. ; Tseng, Chien-Te ; Baker, Susan C. ; Li, Kui. / Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 44. pp. 32208-32221.
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