title: Cooperation between TNF receptor-associated factors 1 and 2 in CD40 signaling.
abstract: TNFR-associated factor 1 (TRAF1) is unique among the TRAF family, lacking most zinc-binding features, and showing marked up-regulation following activation signals. However, the biological roles that TRAF1 plays in immune cell signaling have been elusive, with many reports assigning contradictory roles to TRAF1. The overlapping binding site for TRAFs 1, 2, and 3 on many TNFR superfamily molecules, together with the early lethality of mice deficient in TRAFs 2 and 3, has complicated the quest for a clear understanding of the functions of TRAF1. Using a new method for gene targeting by homologous recombination in somatic cells, we produced and studied signaling by CD40 and its viral oncogenic mimic, latent membrane protein 1 (LMP1) in mouse B cell lines lacking TRAF1, TRAF2, or both TRAFs. Results indicate that TRAFs 1 and 2 cooperate in CD40-mediated activation of the B cell lines, with a dual deficiency leading to a markedly greater loss of function than that of either TRAF alone. In the absence of TRAF1, an increased amount of TRAF2 was recruited to lipid rafts, and subsequently, more robust degradation of TRAF2 and TRAF3 was induced in response to CD40 signaling. In contrast, LMP1 did not require either TRAFs 1 or 2 to induce activation. Taken together, our findings indicate that TRAF1 and TRAF2 cooperate in CD40 but not LMP1 signaling and suggest that cellular levels of TRAF1 may play an important role in modulating the degradation of TRAF2 and TRAF3 in response to signals from the TNFR superfamily.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Hostager
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Munroe
authors.forename: Carissa R
authors.initials: CR
authors.lastname: Moore
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007136:Immunoglobulins / Q000096:biosynthesis / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D007136:Immunoglobulins; D016328:NF-kappa B; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048031:JNK Mitogen-Activated Protein Kinases