title: TRAF3 as a powerful and multitalented regulator of lymphocyte functions.
abstract: This review summarizes the current state of knowledge regarding the roles of the signaling adapter protein tumor necrosis factor receptor (TNFR)-associated factor 3 in regulating the functions of B and T lymphocytes. In B lymphocytes, TNFR-associated factor 3 inhibits signaling by TNFR superfamily receptors, Toll-like receptors, and interleukin-6R. In contrast, signaling to B cells by the virally encoded oncogenic protein latent membrane protein 1 is promoted by TNFR-associated factor 3. An important B cell-specific role for TNFR-associated factor 3 is the inhibition of homeostatic survival, directly relevant to the common occurrence of TNFR-associated factor 3 mutations in human B cell malignancies. TNFR-associated factor 3 was recently found to be a resident nuclear protein in B cells, where it interacts with and inhibits gene expression mediated by the cAMP response element-binding protein transcription complex, including expression of the prosurvival protein myeloid leukemia cell differentiation protein 1. In T lymphocytes, TNFR-associated factor 3 is required for normal signaling by the T cell antigen receptor, while inhibiting signaling by the interleukin-2 receptor. Cytoplasmic TNFR -associated factor 3 restrains nuclear factor-κB2 activation in both T and B cells. Clinical implications and future directions for the study of this context-dependent signaling regulator are discussed.
authors.affiliation: Department of Microbiology, The University of Iowa, Iowa City, Iowa, USA; gail-bishop@uiowa.edu.|Department of Internal Medicine, The University of Iowa, Iowa City, Iowa, USA; and gail-bishop@uiowa.edu.|Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA gail-bishop@uiowa.edu.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival; D005544:Forecasting; D006801:Humans; D007113:Immunity, Innate; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000276:immunology; D051745:Protein Kinase C-delta / Q000276:immunology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D018121:Receptors, Cytokine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D009687:Nuclear Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018121:Receptors, Cytokine; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D014763:Viral Matrix Proteins; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta
keywords: B cell; T cell; signal transduction