Journal article
Reduction of TRAF3 by heterozygosity or aging impacts B cell function
Proceedings of the National Academy of Sciences - PNAS, Vol.122(32), e2507217122
08/12/2025
DOI: 10.1073/pnas.2507217122
PMCID: PMC12358898
PMID: 40773231
Abstract
TNF receptor-associated factor 3 (TRAF3) is a signaling adaptor protein that is ubiquitously expressed but has highly distinct cell type–specific functions. TRAF3 plays critical roles in restraint of B lymphocyte activation, differentiation, and homeostatic survival. Consistent with such roles, loss-of-function mutations in TRAF3 have long been found in various human B cell malignancies. Mice lacking TRAF3 specifically in B cells have autoimmune manifestations, lymphadenopathy, and increased incidence of B cell lymphomas. More recently, human patients with germline TRAF3 mutations leading to haploinsufficiency have been reported; the phenotypes of these patients show striking similarities with those of mice with TRAF3-deficient B cells. This raises the important knowledge gap of how relative quantity of TRAF3 protein regulates B cells. To address this question, we investigated the effect of decreased B cell TRAF3 using mice whose B cells are heterozygous for loss of Traf3. Traf3+/− B cells displayed multiple functional abnormalities, to an extent intermediate between Traf3+/+ and Traf3−/− B cells, indicating a striking dose–response of B cells to relative quantities of TRAF3. Additionally, B cell TRAF3 protein—but not transcript—was reduced in B cells from normal aged mice and humans, consistent with increased occurrence of both B cell hyperactivity and B cell malignancies in older populations. Treatment of aged mice with a proteasome inhibitor restored the level of B cell TRAF3, suggesting age-related chronic signaling through receptors that lead to TRAF3 degradation. Thus, relative levels of B cell TRAF3 protein have important biological impacts on B cell function.
Details
- Title: Subtitle
- Reduction of TRAF3 by heterozygosity or aging impacts B cell function
- Creators
- Emma L Hornick - University of IowaKyp Oxley - University of IowaNathaniel Wieting - University of IowaEmma Treco - University of IowaBruce S Hostager - University of IowaGail A Bishop - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.122(32), e2507217122
- DOI
- 10.1073/pnas.2507217122
- PMID
- 40773231
- PMCID
- PMC12358898
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Publisher
- NATL ACAD SCIENCES; WASHINGTON
- Grant note
- HL007344 / HHS | NIH (NIH) AI162656 / HHS | NIH (NIH) IK6 BX005392 / BLRD VA AI007260 / HHS | NIH (NIH) AG065532 / HHS | NIH (NIH)
- Language
- English
- Date published
- 08/12/2025
- Academic Unit
- Microbiology and Immunology; President; Orthopedics and Rehabilitation; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984945084302771
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