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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

2005; National Academy of Sciences; Volume: 102; Issue: 8 Linguagem: Inglês

10.1073/pnas.0500187102

1091-6490

Julia Hauer, Stephanie Püschner, Parameswaran Ramakrishnan, Ute Simon, Martina Bongers, Christine Federle, Hartmut Engelmann,

Cell death mechanisms and regulation

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 wt 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.