| Epstein-Barr virus is an oncogenic human herpesvirus that infects 90% of the world's population. Latent membrane protein 1 (LMP1) plays a critical role in B cell transformation by EBV and appears to initiate transformation by mimicking a constitutively active CD40 receptor. CD40 is a B cell receptor involved in B cell proliferation and differentiation. We demonstrate the cytoplasmic domain of LMP1 more potently activates c-Jun kinase and NF-κB and induces higher levels of B cell activation than CD40 suggesting LMP1 may utilize a modified CD40 signaling pathway. Intracellular TRAF proteins contribute to signaling by both CD40 and LMP1, however, TRAFs 2 and 3 are degraded following CD40 but not LMP1 signaling. Failure to regulate TRAFs may contribute to the enhanced capacity of LMP1 to activate B cells as well as its ability to transform B cells.; CD40 signals are critical to T-dependent B cell proliferation, differentiation, and antigen presentation. Signaling by CD40 involves recruitment of intracellular tumor necrosis factor receptor associated factors (TRAFs). However, these signals subsequently result in degradation of TRAF2 molecules. We demonstrate that this degradation requires binding to CD40, an intact TRAF2 RING finger structure, and is preceded by extensive TRAF2 post-translational modification following its recruitment to CD40 in membrane rafts. TRAF2 degradation is not seen in cells lacking a functional ubiquitin E1 enzyme. Blocking TRAF2 degradation by proteasome inhibition potentiates CD40-induced activation of c-Jun kinase, suggesting that the magnitude of CD40 responses is regulated by TRAF degradation. |
