The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor.
Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T-cells, bone marrow stromal cells, and osteoblasts, regulates the function of dendritic cells (DC) and osteoclasts. The TRANCE receptor (TRANCE-R), recently identified as receptor activator of NF-kappabeta (RANK), activates NF-kappaB, a transcription factor critical in the differentiation and activation of those cells. In this report we identify the TNF receptor-associated factor (TRAF) family of signal transducers as important components of TRANCE-R-mediated NF-kappaB activation. Coimmunoprecipitation experiments suggested potential interactions between the cytoplasmic tail of TRANCE-R with TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6. Dominant negative forms of TRAF2, TRAF5, and TRAF6 and an endogenous inhibitor of TRAF2, TRAF-interacting protein (TRIP), substantially inhibited TRANCE-R-mediated NF-kappaB activation, suggesting a role of TRAFs in regulating DC and osteoclast function. Overexpression of combinations of TRAF dominant negative proteins revealed competition between TRAF proteins for the TRANCE-R and the possibility of a TRAF-independent NF-kappaB pathway. Analysis of TRANCE-R deletion mutants suggested that the TRAF2 and TRAF5 interaction sites were restricted to the C-terminal 93 amino acids (C-region). TRAF6 also complexed to the C-region in addition to several regions N-terminal to the TRAF2 and TRAF5 association sites. Furthermore, transfection experiments with TRANCE-R deletion mutants revealed that multiple regions of the TRANCE-R can mediate NF-kappaB activation.
Laboratory of Immunology, The Rockefeller University, New York, New York 10021, USA.
B R
BR
Wong
R
R
Josien
S Y
SY
Lee
M
M
Vologodskaia
R M
RM
Steinman
Y
Y
Choi
D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000166:cytology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D053245:RANK Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D013489:Suppression, Genetic; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010446:Peptide Fragments; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D053245:RANK Ligand; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D050807:ets-Domain Protein Elk-1