| First Author | Gokhale S | Year | 2020 |
| Journal | J Immunol | Volume | 204 |
| Issue | 2 | Pages | 459-471 |
| PubMed ID | 31826940 | Mgi Jnum | J:282976 |
| Mgi Id | MGI:6384482 | Doi | 10.4049/jimmunol.1900658 |
| Citation | Gokhale S, et al. (2020) Elevated Choline Kinase alpha-Mediated Choline Metabolism Supports the Prolonged Survival of TRAF3-Deficient B Lymphocytes. J Immunol 204(2):459-471 |
| abstractText | 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 alpha, 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. |
