Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2.
Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2.
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DOI：
10.1016/j.celrep.2015.06.042
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发表时间：
2015-07-21
期刊：
影响因子：
8.8
通讯作者：
Tu BP
中科院分区：
文献类型：
--
作者：
Dutchak PA;Laxman S;Estill SJ;Wang C;Wang Y;Wang Y;Bulut GB;Gao J;Huang LJ;Tu BP
氮通透酶调节因子样2（NPRL 2）是一种保守复合物的组分，其响应于氨基酸不足而抑制mTORC 1（雷帕霉素复合物1的哺乳动物靶标）。在这里，我们表明，NPRL 2是必需的小鼠的生存能力和它的缺乏显着损害胚胎发育中的胎肝造血。此外，NPRL2 KO胚胎具有显著降低的甲硫氨酸水平，并表现出令人联想到钴胺素（维生素B12）缺乏的表型。与这一想法一致，NPRL 2 KO肝脏和小鼠胚胎成纤维细胞（MEF）显示钴胺素转运蛋白转钴胺素2的加工缺陷，沿着受损的溶酶体酸化和溶酶体基因表达。NPRL2 KO MEFs在从高半胱氨酸合成蛋氨酸的钴胺素依赖性合成中表现出显著缺陷，这可以通过补充氰钴胺素来挽救。总之，这些发现证明了NPRL 2和mTORC 1在调节溶酶体依赖性钴胺素加工、甲硫氨酸合成和维持细胞再甲基化潜力中的作用，这在造血过程中很重要。
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 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.