Exploitation of the MEK/ERK Pathway by the Primate Gammaherpesvirus, Rhesus Monkey Rhadinovirus

Rhesus monkey rhadinovirus (RRV) is the primate homolog of the human pathogen, Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of three human malignancies, most notably Kaposi's sarcoma (KS). Primary KSHV infection is marked by transient expression of a subset of lytic viral genes, followed by the establishment of latency. Since de novo RRV infection leads to robust lytic replication yielding high titers, it has become a tractable model system for studying gammaherpesvirus structure and assembly. Our laboratory previously identified at least 33 virally-encoded proteins that comprise the purified RRV particle, but also a small, select subset of cellular proteins, which is the main focus of this dissertation. Though ERK2 is incorporated into other viral particles, this study represents the first to detect phosphorylated/activated ERK2 (pERK2) within a herpesvirus particle. We demonstrated that pERK2 was selectively packaged over pERK1 into the tegument layer of RRV; however, KSHV particles only contained pERK1. In addition, ERK2 was preferentially activated in response to RRV infection and this activation was sustained through a mechanism previously described for KSHV involving the viral tegument protein, ORF45. Our results, along with previously published KSHV studies, indicated the importance of the MEK/ERK pathway in lytic viral gene expression of gammaherpesviruses, but this is the first report to describe a novel and distinct function for ERK1 in virus production. In the final section of this dissertation, we focused our attention on another cellular protein incorporated into both KSHV and RRV particles, the E2 SUMO-conjugating iii enzyme, Ubc9. In addition, we detected SUMO-2/3 in RRV particles as well as several sumoylated proteins, though the identity of these proteins has not been determined. In conclusion, in light of the fact that both the MEK/ERK pathway and the SUMO-modification pathway have been shown to be important in the viral life cycle, we predict that the cellular proteins selectively incorporated in gammaherpesvirus particles may point to cellular processes and signaling pathways that are important in infection.

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