| First Author | Whillock AL | Year | 2021 |
| Journal | J Biol Chem | Pages | 100465 |
| PubMed ID | 33639170 | Mgi Jnum | J:304820 |
| Mgi Id | MGI:6512688 | Doi | 10.1016/j.jbc.2021.100465 |
| Citation | Whillock AL, et al. (2021) TNF receptor-associated factor 3 restrains B cell receptor signaling in normal and malignant B cells. J Biol Chem :100465 |
| abstractText | 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 non-canonical NF-kappaB 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 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. |
