CD40 signaling through a newly identified tumor necrosis factor receptor-associated factor 2 (TRAF2) binding site

Tumor necrosis factor receptor-associated factors (TRAFs) belong to a family of adapter proteins that are involved in tumor necrosis factor receptor superfamily signaling. It has been shown that the recruitment of TRAFs to the CD40 cytoplasmic tail is essential for CD40-mediated B cell responses. However, it has also been shown that some early B cell responses, such as up-regulation of cell surface molecules and B cell proliferation are only marginally impaired by the disruption of previously defined TRAF binding sites (Ahonen, C., Manning, E., Erickson, L.D., O'Connor, B.P., Lind, E.F., Pullen, S.S., Kehry, M.R., and Noelle, R. J. (2002) Nat. Immunol. 3, 451-456; and Manning, E., Pullen, S.S., Souza, D. J., Kehry, M., and Noelle, R. J. (2002) Eur. J. Immunol. 32, 39-49). In this report, we identify a second TRAF2 binding site in the CD40 C terminus. The binding motif "SVQE" fits into the major TRAF2 binding consensus sequence, and its disruption resulted in the loss of remaining CD40 functions. Hence, like CD30, the CD40 cytoplasmic tail contains two distinct and functionally important TRAF2 binding sites.