Regulation of Ribosome Biogenesis During Stress

摘要 综合应激反应(ISR)重新编程细胞基因表达，以促进存活，直到短暂 压力已经过去了。ISR的一个主要目标是将细胞能量储备从促进生长的途径重新定向 走向支持生存的道路。因为核糖体的生物发生是一项令人难以置信的能源密集型任务和质量 生长过程中最需要产生新的核糖体，因此核糖体的生物发生是不足为奇的。 在压力下进行调节。然而，这一规定是如何完成的，以及它如何与ISR交织在一起是 未知。核糖体由4个非编码RNA(RRNA)和80个核糖体蛋白(RP)组成。恰如其分 RRNA和RP合成的协调对细胞动态平衡至关重要。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，只会进一步加剧对细胞的侮辱。 本文提供的数据表明，血管生成素(Ang)是ISR期间核糖体生物发生的主要调节因子。我们 先前发现Ang是在ISR过程中裂解tRNAs产生一系列新的小RNA的蛋白质 称为tRNA衍生的应激诱导RNAs(TiRNAs)。我们已经证明，在翻译过程中，tiRNAs抑制翻译 应激反应和Y盒结合蛋白1(YB1)参与了这一途径。这里提供的数据显示 第二种蛋白质，细胞核酸结合蛋白(CNBP)，也是这一途径的一个组成部分。我们也 研究表明，在应激反应过程中，tiRNAs特异性地调节RPS的翻译。此外，我们 证明YB1在RP生物合成中具有一定作用。最后，在未受压力的细胞中，血管紧张素转换酶促进其表达 通过一种未知的机制产生rRNA。这里提供的数据表明Ang是一种rRNA加工酶 并且，在激活ISR时，rRNA处理被抑制。这允许RP和rRNA的共同调节 综合。这项建议将研究1)tiRNAs如何在应激状态下具体调控RP翻译，2) 确定YB1在核糖体生物发生中的作用，以及3)展示rRNA加工是如何调控的 并确定血管紧张素转换酶在这一过程中的作用。

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.