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Journal of Virology, March 2007, p. 2117-2127, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01961-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Downregulation of Gamma Interferon Receptor 1 by Kaposi's Sarcoma-Associated Herpesvirus K3 and K5{triangledown}

Qinglin Li,1 Robert Means,2 Sabine Lang,2 and Jae U. Jung1*

Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, Massachusetts 01772,1 Department of Pathology, Yale Medical School, New Haven, Connecticut 06520-80232

Received 8 September 2006/ Accepted 27 November 2006

Upon viral infection, the major defense mounted by the host immune system is activation of the interferon (IFN)-mediated antiviral pathway. In order to complete their life cycles, viruses must modulate the host IFN-mediated immune response. The K3 and K5 proteins of a human tumor-inducing herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), have been shown to downregulate the surface expression of host immune modulatory receptors by increasing their endocytosis rates, which leads to suppression of cell-mediated immunity. In this report, we demonstrate that K3 and K5 both specifically target gamma interferon receptor 1 (IFN-{gamma}R1) and induce its ubiquitination, endocytosis, and degradation, resulting in downregulation of IFN-{gamma}R1 surface expression and, thereby, inhibition of IFN-{gamma} action. Mutational analysis indicated that K5 appeared to downregulate IFN-{gamma}R1 more strongly than K3 and that the amino-terminal ring finger motif and the carboxyl-terminal region of K5 were necessary for IFN-{gamma}R1 downregulation. These results suggest that KSHV K3 and K5 suppress both cytokine-mediated and cell-mediated immunity, which ensures efficient viral avoidance of host immune controls.

* Corresponding author. Mailing address: Tumor Virology Division, New England Regional Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772. Phone: (508) 624-8083. Fax: (508) 786-1416. E-mail: jae_jung{at}hms.harvard.edu.

{triangledown} Published ahead of print on 13 December 2006.

Journal of Virology, March 2007, p. 2117-2127, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01961-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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