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Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus.
J Biol Chem. 2007 Nov 02; 282(44):32208-21.JB

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.

Authors+Show Affiliations

Department of Microbiology and Immunology, Center of Biodefense and Emerging Infectious Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17761676

Citation

Devaraj, Santhana G., et al. "Regulation of IRF-3-dependent Innate Immunity By the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus." The Journal of Biological Chemistry, vol. 282, no. 44, 2007, pp. 32208-21.
Devaraj SG, Wang N, Chen Z, et al. Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J Biol Chem. 2007;282(44):32208-21.
Devaraj, S. G., Wang, N., Chen, Z., Chen, Z., Tseng, M., Barretto, N., Lin, R., Peters, C. J., Tseng, C. T., Baker, S. C., & Li, K. (2007). Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. The Journal of Biological Chemistry, 282(44), 32208-21.
Devaraj SG, et al. Regulation of IRF-3-dependent Innate Immunity By the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus. J Biol Chem. 2007 Nov 2;282(44):32208-21. PubMed PMID: 17761676.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. AU - Devaraj,Santhana G, AU - Wang,Nan, AU - Chen,Zhongbin, AU - Chen,Zihong, AU - Tseng,Monica, AU - Barretto,Naina, AU - Lin,Rongtuan, AU - Peters,Clarence J, AU - Tseng,Chien-Te K, AU - Baker,Susan C, AU - Li,Kui, Y1 - 2007/08/30/ PY - 2007/9/1/pubmed PY - 2007/12/14/medline PY - 2007/9/1/entrez SP - 32208 EP - 21 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 282 IS - 44 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/17761676/Regulation_of_IRF_3_dependent_innate_immunity_by_the_papain_like_protease_domain_of_the_severe_acute_respiratory_syndrome_coronavirus_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17761676 DB - PRIME DP - Unbound Medicine ER -