STP-C, an oncoprotein of herpesvirus saimiri augments the activation of NF-kappaB through ubiquitination of TRAF6.
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. Previous study has shown that STP-C, an oncoprotein of HVS, activates NF-kappaB signaling pathway. However, the detailed mechanism of STP-C-mediated NF-kappaB activation has not been reported yet. We first report that STP-C interacts with TRAF6 protein in vivo and in vitro and further investigation shows that Glu(12) residue of STP-C is critical for binding to TRAF6. Introduction of ubiquitin together with STP-C augments NF-kappaB activity compared to that of STP-C expression alone. STP-C expression further induces ubiquitination of endogenous TRAF6. In addition, either a deubiquitination enzyme, CYLD or a dominant negative E2-conjugation enzyme reduced NF-kappaB activity in spite of the presence of STP-C, supporting that the interaction between STP-C and TRAF6 induces ubiquitination of TRAF6. NF-kappaB activation by STP-C through the ubiquitinated TRAF6 causes the increased production of IL-8, an inflammatory chemokine and the enhanced expression of costimulatory molecule ICAM, which might ultimately contribute cellular transformation by the exposure of HVS-infected cells with inflammatory microenvironment and chronic activation.
Chung
Young-Hwa
YH
Department of Nanomedical Engineering, Joint Research Center of PNU-Fraunhofer IGB, Pusan National University, Miryang 627-706, Korea. younghc@pusan.ac.kr
Jhun
Byung Hak
BH
Ryu
Su-Chak
SC
Kim
Heui-Soo
HS
Kim
Cheol-Min
CM
Kim
Bong-Seok
BS
Kim
Young-Ok
YO
Lee
Sang Jun
SJ
D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006567:Herpesvirus 2, Saimiriine / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016209:Interleukin-8 / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016209:Interleukin-8; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D005982:Glutathione Transferase