Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism.
Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism.
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骨骼肌特异性真核翻译起始因子2α磷酸化控制氨基酸代谢和成纤维细胞生长因子21介导的非细胞自主能量代谢。
DOI：
10.1096/fj.15-275990
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Oyadomari S
中科院分区：
文献类型：
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作者：
Miyake M;Nomura A;Ogura A;Takehana K;Kitahara Y;Takahara K;Tsugawa K;Miyamoto C;Miura N;Sato R;Kurahashi K;Harding HP;Oyadomari M;Ron D;Oyadomari S
真核翻译起始因子2α（eIF 2 α）磷酸化依赖性整合应激反应（ISR）是未折叠蛋白反应的一个组成部分，长期以来人们一直知道它可以调节中间代谢，但具体细节还很难说清楚。我们报告了携带eIF 2 α蛋白激酶R样ER激酶的配体激活的骨骼肌特异性衍生物的转基因小鼠的mRNA谱显示了参与氨基酸生物合成和转运的基因的预期上调，但也揭示了肌因子成纤维细胞生长因子21（FGF 21）的诱导表达和分泌，其刺激能量消耗并预防肥胖。通过在基于细胞的筛选中鉴定促进Fgf 21表达的小分子ISR激活剂以及在该过程中暗示ISR诱导型激活转录因子4，进一步加强了ISR和FGF 21表达之间的联系。我们的研究结果表明，eIF 2 α磷酸化不仅调节细胞自主的蛋白质稳态和氨基酸代谢，而且还通过诱导表达一种有效的肌因子影响非细胞自主的代谢调节。Miyake，M.，Nomura，A.，Ogura，A.，Takehana，K.，北原，Y.，Takahara，K.，Tsugawa，K.，Miyamoto，C.，Miura，N.，佐藤河，巴西-地Kurahashi，K.，哈丁，H。P.，Oyadomari，M.，罗恩博士，奥亚多马里，S.骨骼肌特异性真核翻译起始因子2α磷酸化调控氨基酸代谢和成纤维细胞生长因子21介导的非细胞自主能量代谢
The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle–specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non–cell-autonomous metabolic regulation by induced expression of a potent myokine.—Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle–specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21–mediated non–cell-autonomous energy metabolism.