Molecular mechanisms of the effect of herpesvirus saimiri protein StpC on the signaling pathway leading to NF-kappaB activation.
Herpesvirus saimiri (Saimiriine herpesvirus-2) causes lethal T lymphoproliferative diseases in the susceptible species and transforms T lymphocytes to continuous growth in vitro. H. saimiri-induced transformation of T cells is becoming an important experimental tool of biomedical research. Two proteins of H. saimiri subgroup C, Tip and StpC, are essential for T cell transformation by this virus. It has been shown previously that StpC transforms fibroblasts, activates NF-kappaB, and binds to tumor necrosis factor (TNF)-receptor-associated factor (TRAF) proteins, but the molecular mechanism of its action remains insufficiently understood. This study further characterized the effect of StpC on NF-kappaB. First, StpC activates NF-kappaB via the consensus pathway involving activation of I-kappaB kinase and subsequent phosphorylation and degradation of I-kappaB in both T lymphoid and epithelial cells. Second, triggering of this pathway by StpC in both T lymphoid and epithelial cells is dependent on the presence of functional NF-kappaB-inducing kinase (NIK). Third, StpC physically interacts with TRAF in epithelial cells, and the effect of StpC on NF-kappaB activity in these cells requires the presence of functional TRAF. Finally the effect of StpC is completely independent of TNF-alpha, a well described stimulus of NF-kappaB activity. Moreover it appears that StpC uncouples stimulation of NF-kappaB activity from TNF-alpha stimulation. Overall these results argue that the effect of StpC on NF-kappaB is similar to the effects of other viral proteins, "usurping" the TRAF/NIK/I-kappaB kinase pathway, and reinforce the notion that the role of StpC in cell transformation by H. saimiri may be mediated by signaling that results in NF-kappaB activation.
Sorokina
Elena M
EM
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Merlo
Joseph J
JJ
Tsygankov
Alexander Y
AY
D002460:Cell Line; D002472:Cell Transformation, Viral; D006566:Herpesviridae Infections / Q000821:virology*; D006567:Herpesvirus 2, Saimiriine / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014412:Tumor Virus Infections / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D014764:Viral Proteins; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human; C092384:tyrosine kinase interacting protein, Saimiriine herpesvirus 2