Abstract
Herpesvirus saimiri (HVS), a member of the gamma-herpesvirus family, encodes an oncoprotein called Saimiri Transforming Protein (STP) which is required for lymphoma induction in non-human primates. However, a detailed mechanism of STP-A11-induced oncogenesis has not been revealed yet. We first report that STP-A11 oncoprotein interacts with TNF-alpha receptor-associated factor (TRAF) 6 in vivo and in vitro. Mutagenesis analysis of the TRAF6-binding motif (10)PQENDE(15) in STP-A11 reveals that Glu (E)(12) residue is critical for binding to TRAF6 and NF-kappaB activation. Interestingly, co-expression of E12A mutant, lack of TRAF6 binding, with cellular Src (Src) results in decreased transcriptional activity of Stat3 and AP-1, a novel target of STP-A11 compared to that of wild type. Furthermore, the presence of STP-A11 enhances the association of TRAF6 with Src and induces the translocation of both TRAF6 and Src to a nonionic detergent-insoluble fraction. Taken together, these studies suggest that STP-A11 oncoprotein up-regulates both NF-kappaB and AP-1 transcription activity through TRAF6, which would ultimately contribute cellular transformation.
Highlights
Despite a structural homology between TNF receptor-associated factor (TRAF) molecules, each TNFreceptor-associated factor (TRAF) harbors a distinct biological function involved in cell death, survival, and immune responses (Bradley and Pober, 2001; Wajant and Scheurich, 2001; Chung et al, 2002)
Saimiri Transforming Protein (STP)-A11 interacts with TRAF6 in vitro and in vivo, leading to NF-κB activation Since it has been reported that a TRAF6-binding motif is structurally distinct from a TRAF2-binding motif (Ye et al, 2002), we wondered whether STPA11 carries a potential binding motif for TRAF6; PxExxE/ We found that STP-A11 contains a potential binding motif for TRAF6 10PQENDE15, which prompted us to investigate the interaction of STP-A11 with TRAF6
E12A mutant lost the binding to TRAF6 (Figure 1D), suggesting that Glu12 of STP-A11 is necessary for TRAF6 binding
Summary
Despite a structural homology between TNF receptor-associated factor (TRAF) molecules, each TRAF harbors a distinct biological function involved in cell death, survival, and immune responses (Bradley and Pober, 2001; Wajant and Scheurich, 2001; Chung et al, 2002). Gene knockout studies have shown that TRAF2 is responsible for JNK activity and TRAF6 is critical for NF- B signaling (Lomaga et al, 1999; Nguyen et al, 1999). TRAF6 functions as an adaptor protein for various receptors such as IL-1/ Toll like-, TNF-related activation-induced cytokine (TRANCE)-, and CD40-receptor, leading to NF- B activation (Lomaga et al, 1999; Nguyen et al, 1999; Jabara et al, 2002). IL-1 has been shown to regulate cytoskeletal organization in osteoclasts via the association of TRAF6 and Src (Nakamura et al, 2002)
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