Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1).
Latent membrane protein 1 (LMP1), encoded by Epstein-Barr virus, is required for EBV-mediated B cell transformation and plays a significant role in the development of posttransplant B cell lymphomas. LMP1 has also been implicated in exacerbation of autoimmune diseases such as systemic lupus erythematosus. LMP1 is a constitutively active functional mimic of the tumor necrosis factor receptor superfamily member CD40, utilizing tumor necrosis factor receptor-associated factor (TRAF) adaptor proteins to induce signaling. However, LMP1-mediated B cell activation is amplified and sustained compared with CD40. We have previously shown that LMP1 and CD40 use TRAFs 1, 2, 3, and 5 differently. TRAF6 is important for CD40 signaling, but the role of TRAF6 in LMP1 signaling in B cells is not clear. Although TRAF6 binds directly to CD40, TRAF6 interaction with LMP1 in B cells has not been characterized. Here we tested the hypothesis that TRAF6 is a critical regulator of LMP1 signaling in B cells, either as part of a receptor-associated complex and/or as a cytoplasmic adaptor protein. Using TRAF6-deficient B cells, we determined that TRAF6 was critical for LMP1-mediated B cell activation. Although CD40-mediated TRAF6-dependent signaling does not require the TRAF6 receptor-binding domain, we found that LMP1 signaling required the presence of this domain. Furthermore, TRAF6 was recruited to the LMP1 signaling complex via the TRAF1/2/3/5 binding site within the cytoplasmic domain of LMP1.
Interdisciplinary Graduate Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa 52242, USA.
Kelly M
KM
Arcipowski
Laura L
LL
Stunz
John P
JP
Graham
Zachary J
ZJ
Kraus
Tony J
TJ
Vanden Bush
Gail A
GA
Bishop
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002472:Cell Transformation, Viral / Q000235:genetics / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins
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