Journal
JOURNAL OF VIROLOGY
Volume 81, Issue 5, Pages 2117-2127Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01961-06
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Funding
- NCI NIH HHS [CA 082057, R01 CA082057, CA 86038, R01 CA031363, CA 102535, CA 91819, R21 CA102535, R01 CA086038, CA 31363, R01 CA091819] Funding Source: Medline
- NCRR NIH HHS [K26 RR000168, P51 RR000168, RR 00168] Funding Source: Medline
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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.
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