Chung Jacky, Bauer Daniel E, Ghamari Alireza, Nizzi Christopher P, Deck Kathryn M, Kingsley Paul D, Yien Yvette Y, Huston Nicholas C, Chen Caiyong, Schultz Iman J, Dalton Arthur J, Wittig Johannes G, Palis James, Orkin Stuart H, Lodish Harvey F, Eisenstein Richard S, Cantor Alan B, Paw Barry H
Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Sci Signal. 2015 Apr 14;8(372):ra34. doi: 10.1126/scisignal.aaa5903.
In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E-binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.
在多细胞生物中，不同细胞类型获取不同氨基酸的机制以及细胞功能如何适应其可用性是生物学中的基本问题。我们发现中性必需氨基酸（NEAA）摄取增加是红细胞生成的关键组成部分。随着红细胞成熟，氨基酸转运蛋白基因Lat3的表达增加，这增加了NEAA的导入。通过药理学抑制或RNAi介导的LAT3敲低导致NEAA摄取不足，通过mTORC1（雷帕霉素复合物1的哺乳动物靶点）/4E-BP（真核翻译起始因子4E结合蛋白）途径，斑马鱼胚胎和小鼠红细胞中的血红蛋白产生出现特异性减少。CRISPR介导的小鼠红细胞中4E-BP家族成员的缺失使它们对mTORC1和LAT3抑制具有抗性，并恢复了血红蛋白的产生。这些结果确定了LAT3在红细胞中的发育作用，并证明mTORC1作为一种稳态传感器，在翻译水平上将血红蛋白产生与NEAAs（特别是L-亮氨酸）的充分摄取联系起来。
