TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappa B pathway by TRAF-binding TNFRs

J Hauer; S Puschner; P Ramakrishnan; U Simon; M Bongers; C Federle; H Engelmann

doi:10.1073/pnas.0500187102

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TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappa B pathway by TRAF-binding TNFRs

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TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappa B pathway by TRAF-binding TNFRs

J Hauer, S Puschner, P Ramakrishnan, U Simon, M Bongers, C Federle and H Engelmann

Proceedings of the National Academy of Sciences of the United States of America, Vol.102(8), pp.2874-2879

Feb/2005

DOI: https://doi.org/10.1073/pnas.0500187102

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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 Rel-dimers, the canonical p50/RelA and the noncanonical p52/ReIB. Here, we show that via TRAM, 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.

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Title: TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappa B pathway by TRAF-binding TNFRs
Creators: J Hauer (null)
S Puschner (null)
P Ramakrishnan (null)
U Simon (null)
M Bongers (null)
C Federle (null)
H Engelmann (null)
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences of the United States of America, Vol.102(8), pp.2874-2879; Feb/2005
Number of pages: 6
Language: English
DOI: https://doi.org/10.1073/pnas.0500187102
Scientific Unit: The Weizmann Institute of Science
Record Identifier: 993264109003596

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