This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Upon viral infection, the major defense mounted by the host immune system is activation of the interferon (IFN)-mediated anti-viral pathway. In order to complete their life cycle, viruses that are obligatory intracellular parasites must modulate 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 rate, which leads to suppression of cell-mediated immunity. In this report, we demonstrate that K3 and K5 both specifically target interferon (IFN) gamma 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 the amino terminal ring finger motif and the carboxyl terminal region of K5 were necessary for IFN gamma-R1 downregulation, and that K5 appeared to downregulate IFN-gamma-R1 more strongly than K3.
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