Elevated choline kinase α–mediated choline metabolism supports the prolonged survival of TRAF3-deficient B lymphocytes

Samantha Gokhale, Wenyun Lu, Sining Zhu, Yingying Liu, Ronald P. Hart, Joshua D. Rabinowitz, Ping Xie

Research output: Contribution to journalArticle

Abstract

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 α, 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.

Original languageEnglish (US)
Pages (from-to)459-471
Number of pages13
JournalJournal of Immunology
Volume204
Issue number2
DOIs
StatePublished - Jan 1 2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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