Hauer, Julia;
Püschner, Stephanie;
Ramakrishnan, Parameswaran;
Simon, Ute;
Bongers, Martina;
Federle, Christine;
Engelmann, Hartmut;
Dinarello, Charles A.
TNF Receptor (TNFR)-Associated Factor (TRAF) 3 Serves as an Inhibitor of TRAF2/5-Mediated Activation of the Noncanonical NF-κB Pathway by TRAF-Binding TNFRs
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Medientyp:
E-Artikel
Titel:
TNF Receptor (TNFR)-Associated Factor (TRAF) 3 Serves as an Inhibitor of TRAF2/5-Mediated Activation of the Noncanonical NF-κB Pathway by TRAF-Binding TNFRs
Beteiligte:
Hauer, Julia;
Püschner, Stephanie;
Ramakrishnan, Parameswaran;
Simon, Ute;
Bongers, Martina;
Federle, Christine;
Engelmann, Hartmut;
Dinarello, Charles A.
Erschienen:
National Academy of Sciences, 2005
Erschienen in:Proceedings of the National Academy of Sciences of the United States of America
Beschreibung:
<p> 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-κB. 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-κB activation by CD40<sub>wt</sub>and CD40 mutants with different TRAF recruitment patterns. Recognized only recently, NF-κB 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-κB pathway. Via TRAF2/5, CD40 activates both the canonical and the noncanonical NF-κB pathways. We observed that TRAF3 specifically blocked the NF-κB 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-κB activation by TRAF3 resulted in enhanced transcriptional activity of TRAF6-mediated canonical NF-κB emanating from CD40. We also observed that 12 TNFR family members (p75TNFR, LTβR, RANK, HVEM, CD40, CD30, CD27, 4- 1BB, GITR, BCMA, OX40, and TACI) are each capable of activating the alternative NF-κB pathway and conclude that TRAF3 serves as a negative regulator of this pathway for all tested receptors. </p>