Molecular mechanisms of the effect of herpesvirus saimiri protein StpC on the signaling pathway leading to NF-kappaB activation

• Published in: The Journal of biological chemistry 2004-04, Vol.279 (14), p.13469
• Main Authors: Sorokina, Elena M, Merlo, Jr, Joseph J, Tsygankov, Alexander Y
• Format: Article
• Language: English
• Subjects: Cell Line; Cell Transformation, Viral; Herpesviridae Infections - virology; Herpesvirus 2, Saimiriine - genetics; Humans; I-kappa B Proteins - metabolism; Kidney - cytology; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; NF-kappaB-Inducing Kinase; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein Serine-Threonine Kinases - metabolism; Proteins - metabolism; Signal Transduction; TNF Receptor-Associated Factor 2; Tumor Virus Infections - virology; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 0021-9258

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.