HVS STP-C ONCOPROTEIN TARGETS TRAFS TO INDUCE CELL GROWTH TRANSFORMATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Several viral proteins have developed diverse strategies for targeting tumor necrosis factor (TNF) receptor-associated factors (TRAFs) to activate NF-kB transcriptional activity, suggesting the importance of this pathway in viral lifecycle and pathogenesis. Although not required for viral replication, Herpesvirus saimiri (HVS) oncoprotein, termed saimiri transforming protein (STP), is necessary for lymphoid cell immortalization in culture and lymphoma induction in primates. We have previously shown that HVS subgroup C STP-C oncoprotein interacts with TRAF2, resulting in the activation of NF-kB activity. In this study, we further elucidated the role of TRAF binding in STP-C signal transduction leading to NF-kB activation and cell growth transformation. We demonstrate that STP-C interacts with TRAF6 through its amino-terminal short sequence P10IE12ETG15 that completely overlaps with the TRAF2-interaction motif. The proline to arginine (P10R) mutation abrogated TRAF2 binding and NF-kB activation. In contrast, the glutamic acid to alanine (E12A) mutation abolished TRAF6 binding but partially abrogated NF-kB activation activity, indicating a major role of TRAF2 in STP-C mediated NF-kB activation. Consistent with this, the induction of NF-kB activity by STP-C was completely impaired in mouse embryonic fibroblasts (MEFs) deficient for TRAF2 and TRAF5 genes but reduced in MEFs deficient for TRAF6 gene. AIDS related.