Characterization of the rhesus fibromatosis herpesvirus MARCH family member rfK3

Retroperitoneal fibromatosis-associated herpesvirus (RFHV) is a γ-herpesvirus of macaques that is closely related to Kaposi's sarcoma-associated herpesvirus (KSHV). Herein, we present characterization of the K3 gene from RFHV, a homologue of the KSHV K3 and K5 genes. Like the KSHV proteins, kK3 and kK5, the rfK3 protein decreases cell surface MHC I levels. Similar to kK5, rfK3 also modulates ICAM-1, but not another kK5 target, B7.2. Inhibitors of dynamin or mutations in the rfK3 RING-CH E3 ubiquitin ligase domain block cellular target regulation, implicating a ubiquitin-dependent, endocytosis-mediated mechanism for target down regulation and degradation. Overall, this manuscript presents the first characterization of a non-human primate virus MARCH family E3 ubiquitin ligase contributing important information about the evolution of immune avoidance strategies in primate viruses and paving the way for an animal model examining the importance of kK3 and kK5 in vivo.