Tumor necrosis factor receptor-associated factor 2 (TRAF2)-deficient B lymphocytes reveal novel roles for TRAF2 in CD40 signaling.
CD40 function is initiated by tumor necrosis factor (TNF) receptor-associated factor (TRAF) adapter proteins, which play important roles in signaling by numerous receptors. Characterizing roles of individual TRAFs has been hampered by limitations of available experimental models and the poor viability of most TRAF-deficient mice. Here, B cell lines made deficient in TRAF2 using a novel homologous recombination system reveal new roles for TRAF2. We demonstrate that TRAF2 participates in synergy between CD40 and B cell antigen receptor signals, and in CD40-mediated, TNF-dependent IgM production. We also find that TRAF2 participates in the degradation of TRAF3 associated with CD40 signaling, a role that may limit inhibitory actions of TRAF3. Finally, we show that TRAF2 and TRAF6 have overlapping functions in CD40-mediated NF-kappaB activation and CD80 up-regulation. These findings demonstrate previously unappreciated roles for TRAF2 in signaling by TNF receptor family members, using an approach that facilitates the analysis of genes critical to the viability of whole organisms.
Hostager
Bruce S
BS
Department of Pediatrics, Interdisciplinary Program in Immunology, University of Iowa, Iowa City 52242, USA.
Haxhinasto
Sokol A
SA
Rowland
Sarah L
SL
Bishop
Gail A
GA
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D018122:B7-1 Antigen / Q000096:biosynthesis; D015153:Blotting, Western; D019013:CD40 Antigens / Q000096:biosynthesis*; D023201:CD40 Ligand / Q000096:biosynthesis; D002460:Cell Line; D005822:Genetic Vectors; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D007313:Insecta; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D013997:Time Factors; D015854:Up-Regulation
D018122:B7-1 Antigen; D019013:CD40 Antigens; D007075:Immunoglobulin M; D016328:NF-kappa B; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D023201:CD40 Ligand; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases