Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2

Paul A. Dutchak, Sunil Laxman, Sandi Jo Estill, Chensu Wang, Yun Wang, Yiguang Wang, Gamze B. Bulut, Jinming Gao, Lily J. Huang, Benjamin P. Tu

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22 Scopus citations

Abstract

Nitrogen permease regulator-like 2 (NPRL2) is a component of a conserved complex that inhibits mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid insufficiency. Here, we show that NPRL2 is required for mouse viability and that its absence significantly compromises fetal liver hematopoiesis in developing embryos. Moreover, NPRL2 KO embryos have significantly reduced methionine levels and exhibit phenotypes reminiscent of cobalamin (vitamin B<inf>12</inf>) deficiency. Consistent with this idea, NPRL2 KO liver and mouse embryonic fibroblasts (MEFs) show defective processing of the cobalamin-transport protein transcobalamin 2, along with impaired lysosomal acidification and lysosomal gene expression. NPRL2 KO MEFs exhibit a significant defect in the cobalamin-dependent synthesis of methionine from homocysteine, which can be rescued by supplementation with cyanocobalamin. Taken together, these findings demonstrate a role for NPRL2 and mTORC1 in the regulation of lysosomal-dependent cobalamin processing, methionine synthesis, and maintenance of cellular re-methylation potential, which are important during hematopoiesis.

Original languageEnglish (US)
Pages (from-to)371-379
Number of pages9
JournalCell Reports
Volume12
Issue number3
DOIs
Publication statusPublished - Jul 21 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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