Regulation of Ribosome Biogenesis During Stress

摘要 整合的应激反应（ISR）重新编程细胞基因表达，以促进生存，直到短暂的 压力已经过去了。ISR的一个主要目的是将细胞能量储备从促生长途径重新定向 走向有利于生存的道路。由于核糖体的生物合成是一项令人难以置信的能量密集型任务， 在生长过程中最需要新的核糖体的产生，因此核糖体的生物合成是不令人惊讶的。 在压力下调节。然而，如何实现这一规定以及它如何与ISR交织在一起， 未知核糖体由4种非编码RNA（rRNA）和80种核糖体蛋白（RP）组成。适当 rRNA和RP合成的协调对于细胞内稳态是关键的。因此，ISR必须共同监管 细胞应激过程中rRNA和RP的合成。如果不这样做，只会进一步加剧细胞损伤。 这里提供的数据确定血管生成素（ANG）作为ISR期间核糖体生物合成的主要调节因子。我们 先前鉴定的ANG是在ISR过程中切割tRNA以产生一组新的小RNA的蛋白质 称为tRNA衍生的应激诱导RNA（tiRNAs）。我们已经证明，tiRNAs抑制翻译过程中， 应激反应和Y盒结合蛋白1（YB1）参与该途径。数据显示， 第二种蛋白质，细胞核酸结合蛋白（CNBP），也是该途径的组成部分。我们也 表明在应激反应期间，tiRNAs特异性地调节RP的翻译。我们还 证明YB1在RP生物合成中具有作用。最后，在未应激的细胞中，ANG促进 通过一种未知的机制。这里提供的数据表明ANG是一种rRNA加工酶 并且，一旦ISR被激活，rRNA加工就被抑制。这允许RP和rRNA的共同调节 合成.该提案将研究1）tiRNAs如何在应激下特异性调节RP翻译，2） 确定YB1在核糖体生物发生中的作用，3）显示rRNA加工如何调节 并确定ANG在这一过程中发挥的作用。

Abstract The integrated stress response (ISR) reprograms cellular gene expression to promote survival until transient stresses have passed. A major aim of the ISR is to redirect cellular energy reserves from pro-growth pathways towards pro-survival pathways. As biogenesis of ribosomes is an incredibly energy intensive task and mass production of new ribosomes are most needed during growth, it is not surprising that ribosome biogenesis is regulated during stress. However, how this regulation is accomplished and how it is intertwined with the ISR is unknown. Ribosomes are composed of 4 non-coding RNAs (rRNAs) and 80 ribosomal proteins (RPs). Proper coordination of rRNA and RP synthesis is critical to cellular homeostasis. Therefore, the ISR must co-regulate rRNA and RP synthesis during cellular stress. Failure to do so would only further compound the cellular insult. Data presented here identifies angiogenin (ANG) as a major regulator of ribosome biogenesis during ISR. We previously identified ANG as the protein that cleaves tRNAs during ISR to produce a set of novel small RNAs called tRNA-derived stress-induced RNAs (tiRNAs). We have shown that tiRNAs inhibit translation during a stress response and that Y-box binding protein 1 (YB1) is involved in this pathway. Data presented here shows that a 2nd protein, cellular nucleic acid binding protein (CNBP), is also a component of this pathway. We also show that during a stress response, tiRNAs specifically regulate the translation of RPs. Further, we demonstrate that YB1 has a role in RP biosynthesis. Finally, in unstressed cells, ANG promotes the expression of rRNA via an unknown mechanism. Data presented here suggests that ANG is an rRNA processing enzyme and, upon activation of the ISR, rRNA processing is inhibited. This allows for co-regulation of RP and rRNA synthesis. This proposal will study 1) How tiRNAs specifically regulate RP translation under stress, 2) Determine the role that YB1 plays in ribosome biogenesis and 3) Show how rRNA processing is regulated under stress and determine the role ANG plays in this process.