The molecular basis of Herpesvirus saimiri oncogenicity

Herpesvirus saimiri (HVS) oncoprotein, termed saimiri transforming protein (STP), is not necessary for viral replication or persistence but is necessary for lymphoid cell immortalization in culture and lymphoma induction in primates. HVS subgroups A and C encode the STP-A and STP-C oncoproteins, respectively. STP-A and STP-C facilitate cell growth transformation through the manipulation of cellular signaling pathways. Therefore, elucidating how STP oncoproteins activate cellular signaling pathways will provide a better understanding of their contribution to HVS pathogenesis. Studies here show that STP-A interacts with cellular TNF receptor associated factors (TRAF2 and TRAF6) and Src family protein tyrosine kinases (SF-PTK) in a genetically and functionally separable manner, and that each interaction constitutively elicits independent cellular signal transduction. Moreover, STP-A and TRAF6 interaction contributed to the majority of NF-κB activation, whereas TRAF2 interaction-played a minor role. In contrast, interaction of STP-A with SF-PTKs through its SH2 binding motif effectively elicited AP-1 and NF-AT transcription factor activities. Both TRAF and SF-PTK signal transductions induced by STP-A were required for the marked increase of intracellular signal transduction. These results demonstrate that STP-A independently targets two cellular signaling molecules and that these activities likely contribute to HVS-mediated lymphoid cell immortalization in culture and lymphoma induction in primates. STP-C also interacts with both TRAF2 and TRAF6 through its amino-terminal short sequence (P 10 IEETG 15 ). Introduction of P 10 R mutation abrogated TRAF2 binding and NF-κB activation. In contrast, the E 12 A mutation abolished TRAF6 binding but only partially abrogated NF-κB activation, indicating a major role of TRAF2 interaction in STP-C mediated NF-κB activation. Cell lines stably expressing wild type STP-C showed increased proliferation compared with those expressing STP-C TRAF-binding mutants. Finally, human primary T lymphocytes were efficiently immortalized by wild type HVS subgroup C, but not by viruses carrying the TRAF-binding mutations in the STP-C gene. Thus, STP-C differentially targets TRAF2 and TRAF6 for its signal transduction; however, both TRAF2 and TRAF6 interactions of STP-C are necessary for cell growth transformation and HVS-induced primary T cell immortalization. Consequently, the HVS STP oncoproteins activate signaling pathways that ultimately contribute to HVS pathogenesis.