Molecular Mechanisms of the Effect of Herpesvirus saimiri Protein StpC on the Signaling Pathway Leading to NF-κB Activation

Abstract

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-κB, 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-κB. First, StpC activates NF-κB via the consensus pathway involving activation of I-κB kinase and subsequent phosphorylation and degradation of I-κB 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-κB-inducing kinase (NIK). Third, StpC physically interacts with TRAF in epithelial cells, and the effect of StpC on NF-κB activity in these cells requires the presence of functional TRAF. Finally the effect of StpC is completely independent of TNF-α, a well described stimulus of NF-κB activity. Moreover it appears that StpC uncouples stimulation of NF-κB activity from TNF-α stimulation. Overall these results argue that the effect of StpC on NF-κB is similar to the effects of other viral proteins, "usurping" the TRAF/NIK/I-κB 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-κB activation.