Journal article
Nuclear TRAF3 is a negative regulator of CREB in B cells
Proceedings of the National Academy of Sciences - PNAS, Vol.113(4), pp.1032-1037
01/26/2016
DOI: 10.1073/pnas.1514586113
PMCID: PMC4743771
PMID: 26755589
Abstract
The adaptor protein TNF receptor-associated factor 3 (TRAF3) regulates signaling through B-lymphocyte receptors, including CD40, BAFF receptor, and Toll-like receptors, and also plays a critical role inhibiting B-cell homoeostatic survival. Consistent with these findings, loss-of-function human TRAF3 mutations are common in B-cell cancers, particularly multiple myeloma and B-cell lymphoma. B cells of B-cell-specific TRAF3(-/-) mice (B-Traf3(-/-)) display remarkably enhanced survival compared with littermate control (WT) B cells. The mechanism for this abnormal homeostatic survival is poorly understood, a key knowledge gap in selecting optimal treatments for human B-cell cancers with TRAF3 deficiency. We show here for the first time to our knowledge that TRAF3 is a resident nuclear protein that associates with the transcriptional regulator cAMP response element binding protein (CREB) in both mouse and human B cells. The TRAF-C domain of TRAF3 was necessary and sufficient to localize TRAF3 to the nucleus via a functional nuclear localization signal. CREB protein was elevated in TRAF3(-/-) B cells, without change in mRNA, but with a decrease in CREB ubiquitination. CREB-mediated transcriptional activity was increased in TRAF3-deficient B cells. Consistent with these findings, Mcl-1, an antiapoptotic target of CREB-mediated transcription, was increased in the absence of TRAF3 and enhanced Mcl-1 was suppressed with CREB inhibition. TRAF3-deficient B cells were also preferentially sensitive to survival inhibition with pharmacologic CREB inhibitor. Our results identify a new mechanism by which nuclear TRAF3 regulates B-cell survival via inhibition of CREB stability, information highly relevant to the role of TRAF3 in B-cell malignancies.
Details
- Title: Subtitle
- Nuclear TRAF3 is a negative regulator of CREB in B cells
- Creators
- Nurbek Mambetsariev - Department of Microbiology, University of Iowa, Iowa City, IA 52242; Immunology Graduate Program, University of Iowa, Iowa City, IA 52242; Medical Scientist Training Program, University of Iowa, Iowa City, IA 52242Wai W Lin - Immunology Graduate Program, University of Iowa, Iowa City, IA 52242Laura L Stunz - Department of Microbiology, University of Iowa, Iowa City, IA 52242; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242Brett M Hanson - Department of Microbiology, University of Iowa, Iowa City, IA 52242Joanne M Hildebrand - Department of Microbiology, University of Iowa, Iowa City, IA 52242Gail A Bishop - Department of Microbiology, University of Iowa, Iowa City, IA 52242; Immunology Graduate Program, University of Iowa, Iowa City, IA 52242; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242; Internal Medicine, University of Iowa, Iowa City, IA 52242; Department of Veterans Affairs Medical Center, Research , Iowa City, IA 52246 gail-bishop@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.113(4), pp.1032-1037
- Publisher
- United States
- DOI
- 10.1073/pnas.1514586113
- PMID
- 26755589
- PMCID
- PMC4743771
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- R01 AI028847 / NIAID NIH HHS T32 AI007485 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS CA97274 / NCI NIH HHS AI028847 / NIAID NIH HHS T32GM007337 / NIGMS NIH HHS CA086862 / NCI NIH HHS T32AI007485 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS R56 AI028847 / NIAID NIH HHS P50 CA097274 / NCI NIH HHS
- Language
- English
- Date published
- 01/26/2016
- Academic Unit
- Microbiology and Immunology; President
- Record Identifier
- 9984001138602771
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