Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 296, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2021.100465
Keywords
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Categories
Funding
- National Cancer Institute [P30CA086862]
- NIH [T32 AI07485, CA97274, AG065532]
- VA Merit Review [I01 BX001702]
- Department of Veterans Affairs
- Department of Defense Congressionally Directed Medical Research Program Horizon Award [W81XWH-19-1-0442]
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development
- Holden Comprehensive Cancer Center at The University of Iowa
- [GM007337]
- [AI007485]
- [AI007533]
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TRAF3 has diverse signaling functions, inhibiting homeostatic survival in B lymphocytes, while enhancing T-cell effector functions. It plays a role in inhibiting noncanonical NF-kappa B activation, CD40 and BAFF-R signaling in B cells, and its absence promotes abnormal survival of malignant B cells.
TRAF3 has diverse signaling functions, which vary by cell type. Uniquely in B lymphocytes, TRAF3 inhibits homeostatic survival. Highlighting the role of TRAF3 as a tumor suppressor, loss-of-function TRAF3 mutations are associated with human B-cell malignancies, while B-cell-specific deletion of TRAF3 in mice leads to autoimmunity and lymphoma development. The role of TRAF3 in inhibiting noncanonical NF-kappa B activation, CD40 and BAFF-R signaling to B cells is well documented. In contrast, TRAF3 enhances many T-cell effector functions, through associating with and enhancing signaling by the T-cell receptor (TCR)-CD28 complex. The present study was designed to determine the role of TRAF3 in signaling via the B-cell antigen receptor (BCR). The BCR is crucial for antigen recognition, survival, proliferation, and antibody production, and defects in BCR signaling can promote abnormal survival of malignant B cells. Here, we show that TRAF3 is associated with both CD79B and the BCR-activated kinases Syk and Btk following BCR stimulation. BCR-induced phosphorylation of Syk and additional downstream kinases was increased in TRAF3(-/-) B cells, with regulation observed in both follicular and marginal zone B-cell subsets. BCR stimulation of TRAF3(-/-) B cells resulted in increased surface expression of MHC-II, CD80, and CD86 molecules. Interestingly, increased survival of TRAF3(-/-) primary B cells was resistant to inhibition of Btk, while TRAF3-deficient malignant B-cell lines showed enhanced sensitivity. TRAF3 serves to restrain normal and malignant BCR signaling, with important implications for its role in normal B-cell biology and abnormal survival of malignant B cells.
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