Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2.

TitleRegulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2.
Publication TypeJournal Article
Year of Publication2015
AuteursDutchak, P, Laxman, S, Estill, SJo, Wang, C, Wang, Y, Wang, Y, Bulut, GB, Gao, J, Huang, LJ, Tu, BP
JournalCell Rep
Volume12
Issue3
Pagination371-9
Date Published2015 Jul 21
ISSN2211-1247
KeywordsAnimals, Female, Hematopoiesis, Mechanistic Target of Rapamycin Complex 1, Methionine, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins
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 B12) 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.

DOI10.1016/j.celrep.2015.06.042
Alternate JournalCell Rep
PubMed ID26166573
PubMed Central IDPMC4830278
Grant ListR01 HL089966 / HL / NHLBI NIH HHS / United States
R01 GM094314 / GM / NIGMS NIH HHS / United States
R01EB013149 / EB / NIBIB NIH HHS / United States
R01HL089966 / HL / NHLBI NIH HHS / United States
R01 CA185169 / CA / NCI NIH HHS / United States