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Proc Natl Acad Sci U S A ; 102(8): 2874-9, 2005 Feb 22.
Article in English | MEDLINE | ID: mdl-15708970

ABSTRACT

TNF family members and their receptors contribute to increased gene expression for inflammatory processes and intracellular cascades leading to programmed cell death, both via activation of NF-kappaB. TNF receptor (TNFR)-associated factors (TRAFs) are cytoplasmic adaptor proteins binding to various receptors of the TNFR family. In an attempt to delineate the role of individual TRAFs, we compared NF-kappaB activation by CD40(wt) and CD40 mutants with different TRAF recruitment patterns. Recognized only recently, NF-kappaB signaling occurs at least via two different pathways. Each pathway results in nuclear translocation of two different Reldimers, the canonical p50/RelA and the noncanonical p52/RelB. Here, we show that via TRAF6, CD40 mediates only the activation of the canonical NF-kappaB pathway. Via TRAF2/5, CD40 activates both the canonical and the noncanonical NF-kappaB pathways. We observed that TRAF3 specifically blocked the NF-kappaB activation via TRAF2/5. This inhibitory effect of TRAF3 depends on the presence of an intact zinc finger domain. Paradoxically, suppression of TRAF2/5-mediated NF-kappaB activation by TRAF3 resulted in enhanced transcriptional activity of TRAF6-mediated canonical NF-kappaB emanating from CD40. We also observed that 12 TNFR family members (p75TNFR, LTbetaR, RANK, HVEM, CD40, CD30, CD27, 4-1BB, GITR, BCMA, OX40, and TACI) are each capable of activating the alternative NF-kappaB pathway and conclude that TRAF3 serves as a negative regulator of this pathway for all tested receptors.


Subject(s)
NF-kappa B/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/metabolism , TNF Receptor-Associated Factor 2/physiology , Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/physiology , CD40 Antigens/physiology , Cell Line , Humans , TNF Receptor-Associated Factor 2/antagonists & inhibitors , TNF Receptor-Associated Factor 3 , TNF Receptor-Associated Factor 5/antagonists & inhibitors , TNF Receptor-Associated Factor 5/physiology , TNF Receptor-Associated Factor 6/metabolism
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