Nuclear TRAF3 is a negative regulator of CREB in B cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-01, Vol.113 (4), p.1032-1037
• Main Authors: Mambetsariev, Nurbek, Lin, Wai W., Stunz, Laura L., Hanson, Brett M., Hildebrand, Joanne M., Bishop, Gail A.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; B-Lymphocytes - physiology; Binding sites; Biological Sciences; Cell Line; Cell Survival; Cyclic AMP Response Element-Binding Protein - physiology; Humans; Lymphoma, B-Cell - etiology; Mice; Mice, Inbred C57BL; Middle Aged; Multiple myeloma; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Nuclear Localization Signals; Nuclear Proteins - physiology; Proteins; T cell receptors; TNF Receptor-Associated Factor 3 - physiology; Tumor necrosis factor-TNF
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1514586113

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.