TRAF2, Master Regulator of NF-κB

Science's STKE  23 Nov 2004:
Vol. 2004, Issue 260, pp. tw418
DOI: 10.1126/stke.2602004tw418

TRAF2 is an adaptor protein and ubiquitin ligase that is involved in mediating signals from the tumor necrosis factor receptors (TNFRs). Grech et al. investigated B cell signaling and proliferation in TRAF2-deficient mice. TRAF2-deficient B cells accumulated in conditionally deficient mice, leading to enlarged spleen and lymph nodes. Analysis of the TRAF2-deficient B cells showed that the processing of NF-κB2 p100 precursor into the cleaved p52 subunit was increased along with an increase in the DNA-binding activity of the p52 and RelB subunits, which indicates constitutive activation of the noncanonical NF-κB pathway. In addition, the cells were defective in activation of the canonical NF-κB pathway by antibodies that activate the TNFR family member, CD40, and did not show stimulation of proliferation, an increase in RelA activation, or phosphorylation and degradation of IκBα, the inhibitor of NF-κB, that occurs in wild-type cells. Processing of the NF-κB precursor was not further stimulated by BAFF, a ligand for another member of the TNFR family that signals through the noncanonical pathway, or antibodies to CD40, suggesting that in the absence of TRAF2, processing of NF-κB is already maximal. BAFF and the noncanonical NF-κB pathway are involved in B cell maturation, and this pathway appears to be negatively regulated by TRAF2. In contrast, B cell activation through CD40 signaling to the canonical NF-κB pathway requires TRAF2 and is stimulated by TRAF2-mediated signaling. Thus, TRAF2 acts as a dual functional regulator of the NF-κB pathways.

A. R. Grech, M. Amesbury, T. Chan, S. Gardam, A. Basten, R. Brink, TRAF2 differentially regulates the canonical and noncanonical pathways of NF-κB activation in mature B cells. Immunity 21, 629-642 (2004). [Online Journal]