Downregulation of gamma interferon receptor 1 by Kaposi's sarcoma-associated herpesvirus K3 and K5.
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-gammaR1) and induce its ubiquitination, endocytosis, and degradation, resulting in downregulation of IFN-gammaR1 surface expression and, thereby, inhibition of IFN-gamma action. Mutational analysis indicated that K5 appeared to downregulate IFN-gammaR1 more strongly than K3 and that the amino-terminal ring finger motif and the carboxyl-terminal region of K5 were necessary for IFN-gammaR1 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.
Li
Qinglin
Q
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, USA.
Means
Robert
R
Lang
Sabine
S
Jung
Jae U
JU
D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D007111:Immunity, Cellular; D009154:Mutation; D017471:Receptors, Interferon / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D000096743:Interferon gamma Receptor
D016207:Cytokines; D017874:Immediate-Early Proteins; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D014764:Viral Proteins; D000096743:Interferon gamma Receptor; C456022:K3 protein, Kaposi's sarcoma-associated herpesvirus; C405867:K5 protein, Human herpesvirus 8