Staudacher Jonas J, Naarmann-de Vries Isabel S, Ujvari Stefanie J, Klinger Bertram, Kasim Mumtaz, Benko Edgar, Ostareck-Lederer Antje, Ostareck Dirk H, Bondke Persson Anja, Lorenzen Stephan, Meier Jochen C, Blüthgen Nils, Persson Pontus B, Henrion-Caude Alexandra, Mrowka Ralf, Fähling Michael
Charité - Universitätsmedizin Berlin, Institut für Vegetative Physiologie, Charitéplatz 1, D-10117 Berlin, Germany.
University Hospital Aachen, RWTH Aachen University, Department of Intensive and Intermediate Care, Experimental Research Unit, D-52074 Aachen, Germany.
Nucleic Acids Res. 2015 Mar 31;43(6):3219-36. doi: 10.1093/nar/gkv167. Epub 2015 Mar 8.
Protein synthesis is a primary energy-consuming process in the cell. Therefore, under hypoxic conditions, rapid inhibition of global mRNA translation represents a major protective strategy to maintain energy metabolism. How some mRNAs, especially those that encode crucial survival factors, continue to be efficiently translated in hypoxia is not completely understood. By comparing specific transcript levels in ribonucleoprotein complexes, cytoplasmic polysomes and endoplasmic reticulum (ER)-bound ribosomes, we show that the synthesis of proteins encoded by hypoxia marker genes is favoured at the ER in hypoxia. Gene expression profiling revealed that transcripts particularly increased by the HIF-1 transcription factor network show hypoxia-induced enrichment at the ER. We found that mRNAs favourably translated at the ER have higher conservation scores for both the 5'- and 3'-untranslated regions (UTRs) and contain less upstream initiation codons (uAUGs), indicating the significance of these sequence elements for sustained mRNA translation under hypoxic conditions. Furthermore, we found enrichment of specific cis-elements in mRNA 5'- as well as 3'-UTRs that mediate transcript localization to the ER in hypoxia. We conclude that transcriptome partitioning between the cytoplasm and the ER permits selective mRNA translation under conditions of energy shortage.
蛋白质合成是细胞中一个主要的能量消耗过程。因此，在缺氧条件下，快速抑制整体mRNA翻译是维持能量代谢的一种主要保护策略。目前尚不完全清楚一些mRNA，尤其是那些编码关键生存因子的mRNA，如何在缺氧状态下继续高效翻译。通过比较核糖核蛋白复合物、细胞质多核糖体和内质网（ER）结合核糖体中的特定转录本水平，我们发现缺氧标记基因编码的蛋白质合成在缺氧状态下在内质网中更受青睐。基因表达谱分析显示，特别是由HIF-1转录因子网络上调的转录本在缺氧状态下在内质网中富集。我们发现在内质网中优先翻译的mRNA在5'-和3'-非翻译区（UTR）具有更高的保守性得分，并且含有较少的上游起始密码子（uAUG），这表明这些序列元件在缺氧条件下对mRNA持续翻译具有重要意义。此外，我们发现mRNA的5'-UTR和3'-UTR中存在特定顺式元件的富集，这些元件在缺氧状态下介导转录本定位于内质网。我们得出结论，细胞质和内质网之间的转录组划分允许在能量短缺条件下进行选择性mRNA翻译。
