Ferretti Max B, Ghalei Homa, Ward Ethan A, Potts Elizabeth L, Karbstein Katrin
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, Florida, USA.
The Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida, USA.
Nat Struct Mol Biol. 2017 Sep;24(9):700-707. doi: 10.1038/nsmb.3442. Epub 2017 Jul 31.
We describe a novel approach to separate two ribosome populations from the same cells and use this method in combination with RNA-seq to identify mRNAs bound to Saccharomyces cerevisiae ribosomes with and without Rps26, a protein linked to the pathogenesis of Diamond-Blackfan anemia (DBA). These analyses reveal that Rps26 contributes to mRNA-specific translation by recognition of the Kozak sequence in well-translated mRNAs and that Rps26-deficient ribosomes preferentially translate mRNA from select stress-response pathways. Surprisingly, exposure of yeast to these stresses leads to the formation of Rps26-deficient ribosomes and to the increased translation of their target mRNAs. These results describe a novel paradigm: the production of specialized ribosomes, which play physiological roles in augmenting the well-characterized transcriptional stress response with a heretofore unknown translational response, thereby creating a feed-forward loop in gene expression. Moreover, the simultaneous gain-of-function and loss-of-function phenotypes from Rps26-deficient ribosomes can explain the pathogenesis of DBA.
我们描述了一种从同一细胞中分离出两种核糖体群体的新方法，并将该方法与RNA测序相结合，以鉴定与酿酒酵母核糖体结合的信使核糖核酸（mRNA），这些核糖体含有或不含有与钻石黑范贫血（DBA）发病机制相关的蛋白质Rps26。这些分析表明，Rps26通过识别翻译良好的mRNA中的科扎克序列来促进mRNA特异性翻译，并且缺乏Rps26的核糖体优先翻译来自特定应激反应途径的mRNA。令人惊讶的是，将酵母暴露于这些应激条件下会导致缺乏Rps26的核糖体形成，并增加其靶标mRNA的翻译。这些结果描述了一种新的模式：产生特殊的核糖体，它们在增强已充分表征的转录应激反应方面发挥生理作用，同时伴有迄今未知的翻译反应，从而在基因表达中形成一个前馈环。此外，缺乏Rps26的核糖体同时出现的功能获得和功能丧失表型可以解释DBA的发病机制。
