Molecular Mechanisms of TNFR-associated Factor 6 (TRAF6) Utilization by the Oncogenic Viral Mimic of CD40, Latent Membrane Protein 1 (LMP1)

Kelly M Arcipowski; Laura L Stunz; John P Graham; Zachary J Kraus; Tony J. Vanden Bush; Gail A Bishop

doi:10.1074/jbc.M110.185983

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Molecular Mechanisms of TNFR-associated Factor 6 (TRAF6) Utilization by the Oncogenic Viral Mimic of CD40, Latent Membrane Protein 1 (LMP1)

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Molecular Mechanisms of TNFR-associated Factor 6 (TRAF6) Utilization by the Oncogenic Viral Mimic of CD40, Latent Membrane Protein 1 (LMP1)

Kelly M Arcipowski, Laura L Stunz, John P Graham, Zachary J Kraus, Tony J. Vanden Bush and Gail A Bishop

The Journal of biological chemistry, Vol.286(12), pp.9948-9955

03/25/2011

DOI: 10.1074/jbc.M110.185983

PMCID: PMC3060549

PMID: 21262968

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Abstract

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.

MAP Kinases (MAPKs)

NF-κB

Receptor Regulation

Latent Membrane Protein 1

Immunology

Signal Transduction

TRAF

Cell Surface Receptor

Lymphocyte

Adapter Protein

Details

Title: Subtitle: Molecular Mechanisms of TNFR-associated Factor 6 (TRAF6) Utilization by the Oncogenic Viral Mimic of CD40, Latent Membrane Protein 1 (LMP1)
Creators: Kelly M Arcipowski - Molecular and Cellular Biology and
Laura L Stunz - Microbiology and
John P Graham - Immunology and
Zachary J Kraus - Immunology and
Tony J. Vanden Bush - Microbiology and
Gail A Bishop - Veterans Affairs Medical Center, Iowa City, Iowa 52242
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.286(12), pp.9948-9955
DOI: 10.1074/jbc.M110.185983
PMID: 21262968
PMCID: PMC3060549
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: CA099997; T32AI007533-12 / National Institutes of Health
Alternative title: TRAF6 in LMP1 Signaling
Language: English
Date published: 03/25/2011
Academic Unit: Microbiology and Immunology; President
Record Identifier: 9984001147902771

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