Intestinal Amino Acid Availability via PEPT-1 Affects TORC1/2 Signaling and the Unfolded Protein Response
Intestinal Amino Acid Availability via PEPT-1 Affects TORC1/2 Signaling and the Unfolded Protein Response
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DOI：
10.1021/pr5002669
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发表时间：
2014-08-01
影响因子：
4.4
通讯作者：
Spanier, Britta
中科院分区：
文献类型：
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作者：
Geillinger, Kerstin E.;Kuhlmann, Katja;Spanier, Britta
肠道肽转运蛋白PEPT-1在秀丽隐杆线虫的发育、生长、繁殖和应激耐受中起着重要作用，如pept-1缺陷株的严重表型所揭示的。研究表明，后代数量减少和应激抵抗力增加是胰岛素/IGF信号级联反应变化的结果。为了进一步阐明PEPT 1缺陷动物表型改变背后的调控网络，应用了定量蛋白质组分析与转录组分析相结合。XBP-1的各种靶基因，未折叠蛋白反应的主要介质，被发现在mRNA和蛋白质水平下调，伴随着剪接的xbp-1 mRNA的减少。蛋白质组分析也显示了许多核糖体蛋白的含量显着减少。这与pept-1C中蛋白质合成速率的降低有关。这是一个严格受TOR（雷帕霉素靶蛋白）复合物（游离氨基酸的细胞传感器）调控的过程。这些数据表明PEPT-1在细胞氨基酸稳态中起着重要作用。在PEPT-1缺乏症中，氨基酸水平系统性下降，导致蛋白质合成和IRE-1/XBP-1途径的改变。
The intestinal peptide transporter PEPT-1 plays an important role in development, growth, reproduction, and stress tolerance in Caenorhabditis elegans, as revealed by the severe phenotype of the pept-1-deficient strain. The reduced number of offspring and increased stress resistance were shown to result from changes in the insulin/IGF-signaling cascade. To further elucidate the regulatory network behind the phenotypic alterations in PEPT1-deficient animals, a quantitative proteome analysis combined with transcriptome profiling was applied. Various target genes of XBP-1, the major mediator of the unfolded protein response, were found to be downregulated at the mRNA and protein levels, accompanied by a reduction of spliced xbp-1 mRNA. Proteome analysis also revealed a markedly reduced content of numerous ribosomal proteins. This was associated with a reduction in the protein synthesis rate in pept-1 C. elegans, a process that is strictly regulated by the TOR (target of rapamycine) complex, the cellular sensor for free amino acids. These data argue for a central role of PEPT-1 in cellular amino acid homeostasis. In PEPT-1 deficiency, amino acid levels dropped systematically, leading to alterations in protein synthesis and in the IRE-1/XBP-1 pathway.