Journal
JOURNAL OF IMMUNOLOGY
Volume 204, Issue 2, Pages 459-471Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1900658
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Funding
- National Institutes of Health (NIH) [R01 CA158402]
- Department of Defense [W81XWH-13-1-0242]
- Pilot Award of the Cancer Institute of New Jersey from the National Cancer Institute (NCI) [P30CA072720]
- Busch Biomedical Grant
- NCI [R50 CA211437]
- NIH [R01 ES026057]
- Flow Cytometry Core Facility
- NCI-Cancer Center Support Grant [P30CA072720]
- Rutgers Cancer Institute of New Jersey Metabolomics Shared Resource
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Specific deletion of the tumor suppressor TRAF3 from B lymphocytes in mice leads to the prolonged survival of mature B cells and expanded B cell compartments in secondary lymphoid organs. In the current study, we investigated the metabolic basis of TRAF3-mediated regulation of B cell survival by employing metabolomic, lipidomic, and transcriptomic analyses. We compared the polar metabolites, lipids, and metabolic enzymes of resting splenic B cells purified from young adult B cell-specific Traf3(-/-) and littermate control mice. We found that multiple metabolites, lipids, and enzymes regulated by TRAF3 in B cells are clustered in the choline metabolic pathway. Using stable isotope labeling, we demonstrated that phosphocholine and phosphatidylcholine biosynthesis was markedly elevated in Traf3(-/-) mouse B cells and decreased in TRAF3-reconstituted human multiple myeloma cells. Furthermore, pharmacological inhibition of choline kinase a, an enzyme that catalyzes phosphocholine synthesis and was strikingly increased in Traf3(-/-) B cells, substantially reversed the survival phenotype of Traf3(-/-) B cells both in vitro and in vivo. Taken together, our results indicate that enhanced phosphocholine and phosphatidylcholine synthesis supports the prolonged survival of Traf3(-/-) B lymphocytes. Our findings suggest that TRAF3-regulated choline metabolism has diagnostic and therapeutic value for B cell malignancies with TRAF3 deletions or relevant mutations.
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