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Journal of Virology, July 2009, p. 6689-6705, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02220-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Severe Acute Respiratory Syndrome Coronavirus Papain-Like Protease Ubiquitin-Like Domain and Catalytic Domain Regulate Antagonism of IRF3 and NF-{kappa}B Signaling{triangledown} ,{dagger}

Matthew Frieman,1 Kiira Ratia,2 Robert E. Johnston,3 Andrew D. Mesecar,2 and Ralph S. Baric1*

Department of Epidemiology, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599,1 Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois 60607,2 Carolina Vaccine Institute and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 275993

Received 21 October 2008/ Accepted 8 April 2009

The outcome of a viral infection is regulated in part by the complex coordination of viral and host interactions that compete for the control and optimization of virus replication. Severe acute respiratory syndrome coronavirus (SARS-CoV) intimately engages and regulates the host innate immune responses during infection. Using a novel interferon (IFN) antagonism screen, we show that the SARS-CoV proteome contains several replicase, structural, and accessory proteins that antagonize the IFN pathway. In this study, we focus on the SARS-CoV papain-like protease (PLP), which engages and antagonizes the IFN induction and NF-{kappa}B signaling pathways. PLP blocks these pathways by affecting activation of the important signaling proteins in each pathway, IRF3 and NF-{kappa}B. We also show that the ubiquitin-like domain of PLP is necessary for pathway antagonism but not sufficient by itself to block these pathways regardless of the enzymatic activity of the protease. The potential mechanism of PLP antagonism and its role in pathogenesis are discussed.

* Corresponding author. Mailing address: Department of Epidemiology, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599. Phone: (919) 966-3895. Fax: (919) 966-2089. E-mail: rbaric{at}email.unc.edu

{triangledown} Published ahead of print on 15 April 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, July 2009, p. 6689-6705, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02220-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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