TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs.
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.
Hauer
Julia
J
Institut für Immunologie der Universität München, Goethestrasse 31, 80366 Munich, Germany.
Püschner
Stephanie
S
Ramakrishnan
Parameswaran
P
Simon
Ute
U
Bongers
Martina
M
Federle
Christine
C
Engelmann
Hartmut
H
D019013:CD40 Antigens / Q000502:physiology; D002460:Cell Line; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3; D048015:TNF Receptor-Associated Factor 5 / Q000037:antagonists & inhibitors / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology*
D019013:CD40 Antigens; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; C090656:TRAF3 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins