title: Nuclear TRAF3 is a negative regulator of CREB in B cells.
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.
authors.affiliation: 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 52242;
authors.forename: Nurbek
authors.initials: N
authors.lastname: Mambetsariev
authors.affiliation: Immunology Graduate Program, University of Iowa, Iowa City, IA 52242;
authors.forename: Wai W
authors.initials: WW
authors.lastname: Lin
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242;
authors.forename: Laura L
authors.initials: LL
authors.lastname: Stunz
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242;
authors.forename: Brett M
authors.initials: BM
authors.lastname: Hanson
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242;
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Hildebrand
authors.affiliation: 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 (151), Iowa City, IA 52246 gail-bishop@uiowa.edu.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3 / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human
keywords: B cell; CREB; TRAF3