Journal article
TNF receptor-associated factor 3 restrains B-cell receptor signaling in normal and malignant B cells
The Journal of biological chemistry, Vol.296, pp.100465-100465
01/2021
DOI: 10.1016/j.jbc.2021.100465
PMCID: PMC8042179
PMID: 33639170
Abstract
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-κB 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.
Details
- Title: Subtitle
- TNF receptor-associated factor 3 restrains B-cell receptor signaling in normal and malignant B cells
- Creators
- Amy L. Whillock - University of IowaTiffany K. Ybarra - University of IowaGail A. Bishop - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.296, pp.100465-100465
- DOI
- 10.1016/j.jbc.2021.100465
- PMID
- 33639170
- PMCID
- PMC8042179
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000738, name: Department of Veterans Affairs; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000005, name: US Department of Defense
- Language
- English
- Date published
- 01/2021
- Academic Unit
- Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984297429802771
Metrics
9 Record Views