title: TRAF binding is required for a distinct subset of in vivo B cell functions of the oncoprotein LMP1.
abstract: EBV-encoded latent membrane protein 1 (LMP1) is important for EBV contributions to B cell transformation and many EBV-associated malignancies, as well as EBV-mediated exacerbation of autoimmunity. LMP1 functionally mimics TNF receptor (TNFR) superfamily member CD40, but LMP1 signals and downstream effects are amplified and sustained compared with CD40. CD40 and LMP1 both use TNFR-associated factor (TRAF) adaptor proteins, but in distinct ways. LMP1 functions require TRAFs 3, 5, and 6, which interact with LMP1. However, TRAFs can also contribute to signaling in the absence of direct interactions with cell surface receptors, so we investigated whether their roles in LMP1 in vivo functions require direct association. We show in this study that the LMP1 TRAF binding site was required for LMP1-mediated autoantibody production, the germinal center response to immunization, and optimal production of several isotypes of Ig, but not LMP1-dependent enlargement of secondary lymphoid organs in transgenic mice. Thus, LMP1 in vivo effects can be mediated via both TRAF binding-dependent and -independent pathways. Together with our previous findings, these results indicate that TRAF-dependent receptor functions may not always require TRAF-receptor binding. These data suggest that TRAF-mediated signaling pathways, such as those of LMP1, may be more diverse than previously appreciated. This finding has significant implications for receptor and TRAF-targeted therapies.
authors.affiliation: Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Arcipowski
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D001483:Base Sequence; D001665:Binding Sites; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007074:Immunoglobulin G; D020033:Protein Isoforms; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014763:Viral Matrix Proteins