Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Biol Chem. 2013 Jun 14;288(24):17202-13. doi: 10.1074/jbc.M113.466920. Epub 2013 May 3.
Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing β-cells in type 2 diabetes mellitus. β-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that are mediated via phosphorylation of the translation initiation factor eIF2α. It is reported here that chronic ER stress correlated with increased islet protein synthesis and apoptosis in β-cells in vivo. Paradoxically, chronic ER stress in β-cells induced an anabolic transcription program to overcome translational repression by eIF2α phosphorylation. This program included expression of amino acid transporter and aminoacyl-tRNA synthetase genes downstream of the stress-induced ATF4-mediated transcription program. The anabolic response was associated with increased amino acid flux and charging of tRNAs for branched chain and aromatic amino acids (e.g. leucine and tryptophan), the levels of which are early serum indicators of diabetes. We conclude that regulation of amino acid transport in β-cells during ER stress involves responses leading to increased protein synthesis, which can be protective during acute stress but can lead to apoptosis during chronic stress. These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes.
内质网（ER）应激诱导的反应与 2 型糖尿病中胰岛素产生β细胞的丧失有关。据信，在 ER 应激期间，β细胞的存活取决于通过翻译起始因子 eIF2α 的磷酸化介导的降低蛋白质合成速率。这里报道的是，慢性 ER 应激与体内β细胞中胰岛蛋白合成和细胞凋亡的增加相关。矛盾的是，β细胞中的慢性 ER 应激诱导了一个合成代谢转录程序，以克服 eIF2α 磷酸化引起的翻译抑制。该程序包括应激诱导的 ATF4 介导的转录程序下游的氨基酸转运体和氨酰-tRNA 合成酶基因的表达。合成代谢反应与氨基酸通量的增加以及支链和芳香族氨基酸（例如亮氨酸和色氨酸）的 tRNA 加载有关，这些氨基酸的水平是糖尿病的早期血清指标。我们得出结论，在 ER 应激期间，β细胞中氨基酸转运的调节涉及导致蛋白质合成增加的反应，这在急性应激期间可能具有保护作用，但在慢性应激期间可能导致细胞凋亡。这些研究表明，胰岛中氨基酸转运体的表达增加可以作为糖尿病发展的早期诊断生物标志物。
