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Roles of the TRAF2/3 Binding Site in Differential B Cell Signaling by CD40 and Its Viral Oncogenic Mimic, LMP1¹

John P. Graham^*, Carissa R. Moore^2,* and Gail A. Bishop^3,*,,,

^* Interdisciplinary Program in Immunology, Department of Microbiology, Department of Internal Medicine, the Veterans Affairs Medical Center, Iowa City, Iowa 52242

The EBV protein, latent membrane protein 1 (LMP1), is a functional mimic of the cellular receptor CD40, but signals to B lymphocytes in an amplified and sustained manner compared with CD40. LMP1 contributes to the development of B cell lymphoma in immunosuppressed patients, and may exacerbate flares of certain autoimmune diseases. The cytoplasmic domain of LMP1 binds the signaling adaptor TRAF2 with lower avidity than the cytoplasmic domain of CD40, and TRAF2 is needed for CD40-mediated degradation of TRAFs 2 and 3. LMP1 doesn’t induce TRAF degradation, and employs TRAF3 as a positive mediator of cell signaling, whereas CD40 signals are inhibited by TRAF3. We thus tested the hypothesis that relative affinity for TRAF2, and/or distinct sequence differences in the TRAF2/3 binding sites of CD40 vs LMP1, controls the disparate ways in which CD40 and LMP1 use TRAFs 2 and 3, and their distinct signaling characteristics. CD40 and LMP1 mutants in which the TRAF binding site sequences were swapped were examined, testing TRAF binding and degradation, and induction of B cell activation. Results revealed that TRAF binding affinity and TRAF binding site sequence dictate a distinct subset of CD40 vs LMP1 signaling properties. Examination of TRAF binding, degradation, cytokine production, IgM secretion, and the activation of c-Jun kinase and NF-B revealed that some events are dictated by TRAF binding site sequences, others are partially regulated, and still others are independent of the TRAF binding site sequence.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These studies were supported by National Institutes of Health Grants CA099997 and AI49993 to G.A.B. J.P.G. received support from National Institutes of Health Grant T32 AI007485. C.R.M. received support from National Institutes of Health Grant T32 HL07638–18.

² Current address: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08855.

³ Address correspondence and reprint requests to Dr. Gail A. Bishop, Medical Education and Research Facility, Department of Microbiology, University of Iowa, Iowa City, IA 52242. E-mail address: gail-bishop{at}uiowa.edu

⁴ Abbreviations used in this paper: LMP1, latent membrane protein 1; mCD40, mouse CD40; CY, cytoplasmic; TBS, TRAF binding site; CTAR1 and 2, cytoplasmic activating region 1 and 2; hCD40, human CD40; pJNK, phospho-JNK.