Fundamental connections between protein synthesis and carbohydrate metabolism: eIF4A regulation

蛋白质合成和碳水化合物代谢之间的基本联系：eIF4A 调节

• 批准号: BB/K005979/1
• 负责人: Mark Peter Ashe
• 金额: $ 51.51万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK005979%2F1
• 关键词: Fundamental; connections; between; protein; synthesis

The information carried in the genes from living cells is decoded to produce chains of different amino acids called proteins that dictate the identity and function of that cell. Proteins represent one of the building blocks of all life, catalyzing most of the biochemical reactions as well as serving numerous structural and regulatory roles. An intermediate between the gene and the protein is the messenger RNA (mRNA). In eukaryotic cells (animals, plants and fungi), genes have been segregated into the nucleus away from the machinery involved in protein synthesis allowing independent regulation of mRNA and protein production. The 'translation' of the code contained in the mRNA is a complicated process that is highly similar across eukaryotic cells. All organisms need to be able to adapt to changes in their external environment. This adaptation involves changing the levels of individual proteins within cells. Hence, in response to stresses such as increases in temperature or starvation for certain nutrients, cells rapidly halt the process of protein synthesis to allow a switch to a stress specific protein production pathway. We are studying this regulation of translation using the simple eukaryote, brewer's yeast, as a model organism. Sugars are essential for life. Fundamentally, the breakdown of sugars provides the chemical energy that drives most other processes in living cells. The sugar, glucose, is used as the major source of energy in most living systems from bacteria to humans. For instance, as simple eukaryotic micro-organisms, yeast prefer to grow on glucose as a sugar source. One of the most dramatic decreases in protein production observed in response to stress in yeast occurs rapidly after the depletion of glucose from the growth media. We have recently discovered that a specific and critical translation factor dissociates from the translation machinery after glucose starvation. This factor is called the eukaryotic translation initiation factor 4A (eIF4A). eIF4A is an example of a class of proteins called helicases. These proteins can unwind DNA and RNA molecules, and eIF4A can unwind sections of the mRNA. This is thought to give the translation machinery access and promote the overall transit or 'scanning' of this machinery along the mRNA in search of an initiation site.Therefore in this proposal, we will study how the removal of glucose from yeast cells causes a loss of eIF4A from translating mRNAs. We seek to answer questions relating to what causes this reduction in the level of eIF4A associated with the translation machinery, how important this eIF4A loss is in the inhibition of protein production and whether mRNAs that continue to be translated are bound by eIF4A or other helicases. This project is important because it brings together two pathways that are fundamental to living systems these are the energy generating system and the protein production system. A detailed characterisation of this mechanism in brewer's yeast will facilitate the longer term investigation in other organisms. Should such a pathway of translation control be present in other organisms (possibly activated by different stresses) then it is likely to be very important for the physiology of that organism. Should the pathway prove to be fungal-specific then it might represent a new target for drug design to combat human pathogenic fungi.

来自活细胞的基因携带的信息被解码，以产生被称为蛋白质的不同氨基酸链，这些蛋白质决定了细胞的身份和功能。蛋白质是所有生命的基石之一，催化了大部分的生化反应，并发挥了许多结构和调节作用。基因和蛋白质之间的中间体是信使RNA(信使RNA)。在真核细胞(动物、植物和真菌)中，基因被分离到细胞核中，远离参与蛋白质合成的机制，从而独立地调节信使核糖核酸和蛋白质的产生。包含在信使核糖核酸中的密码的“翻译”是一个复杂的过程，在真核细胞中高度相似。所有的有机体都需要能够适应外部环境的变化。这种适应包括改变细胞内单个蛋白质的水平。因此，为了应对压力，如温度升高或某些营养物质的饥饿，细胞迅速停止蛋白质合成过程，以允许切换到应激特定的蛋白质产生途径。我们正在使用简单的真核生物啤酒酵母作为模式生物来研究这种翻译规则。糖是生命所必需的。从根本上说，糖的分解提供了化学能，推动了活细胞中的大多数其他过程。糖，葡萄糖，在从细菌到人类的大多数生命系统中被用作主要的能量来源。例如，酵母作为简单的真核微生物，更喜欢以葡萄糖为糖源生长。在酵母中观察到的响应压力的蛋白质产量最显著的下降之一发生在生长介质中的葡萄糖耗尽后。我们最近发现，葡萄糖饥饿后，一个特定的和关键的翻译因子从翻译机制中解离出来。这种因子被称为真核细胞翻译起始因子4A(EIF4A)。EIF4A是一类称为解旋酶的蛋白质的一个例子。这些蛋白质可以解开DNA和RNA分子，eIF4A可以解开部分信使核糖核酸。这被认为给翻译机器提供了途径，并促进了这一机器沿着mRNA的整体运输或“扫描”，以寻找起始点。因此，在本提案中，我们将研究酵母细胞中葡萄糖的去除如何导致翻译mRNAs中eIF4A的损失。我们试图回答与翻译机制相关的eIF4A水平下降的原因，这种eIF4A丢失在抑制蛋白质生产中有多重要，以及继续翻译的mRNAs是否与eIF4A或其他解旋酶结合。这个项目很重要，因为它汇集了生命系统的两条基本途径，即能量生成系统和蛋白质生产系统。对啤酒酵母中这一机制的详细描述将有助于在其他生物中进行更长期的研究。如果这样的翻译控制途径在其他生物体中存在(可能被不同的胁迫激活)，那么它可能对该生物体的生理学非常重要。如果该途径被证明是真菌特有的，那么它可能代表着对抗人类致病真菌的药物设计的新靶点。

项目成果

Integrated multi-omics reveals common properties underlying stress granule and P-body formation.

综合的多词揭示了应力颗粒和p体形成的共同特性。

• DOI: 10.1080/15476286.2021.1976986
• 发表时间: 2021-11-12
• 期刊: RNA biology
• 影响因子: 4.1
• 作者: Kershaw CJ;Nelson MG;Lui J;Bates CP;Jennings MD;Hubbard SJ;Ashe MP;Grant CM
• 通讯作者: Grant CM

Global mRNA selection mechanisms for translation initiation.

• DOI: 10.1186/s13059-014-0559-z
• 发表时间: 2015-01-05
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Costello J;Castelli LM;Rowe W;Kershaw CJ;Talavera D;Mohammad-Qureshi SS;Sims PF;Grant CM;Pavitt GD;Hubbard SJ;Ashe MP
• 通讯作者: Ashe MP

Granules harboring translationally active mRNAs provide a platform for P-body formation following stress.

• DOI: 10.1016/j.celrep.2014.09.040
• 发表时间: 2014-11-06
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Lui J;Castelli LM;Pizzinga M;Simpson CE;Hoyle NP;Bailey KL;Campbell SG;Ashe MP
• 通讯作者: Ashe MP

Core Fermentation (CoFe) granules focus coordinated glycolytic mRNA localization and translation to fuel glucose fermentation.

核心发酵（COFE）颗粒聚焦的糖酵解mRNA定位和转化为燃料葡萄糖发酵。

• DOI: 10.1016/j.isci.2021.102069
• 发表时间: 2021-02-19
• 期刊: iScience
• 影响因子: 5.8
• 作者: Morales-Polanco F;Bates C;Lui J;Casson J;Solari CA;Pizzinga M;Forte G;Griffin C;Garner KEL;Burt HE;Dixon HL;Hubbard S;Portela P;Ashe MP
• 通讯作者: Ashe MP

The role of PKA in the translational response to heat stress in Saccharomyces cerevisiae.

• DOI: 10.1371/journal.pone.0185416
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Barraza CE;Solari CA;Marcovich I;Kershaw C;Galello F;Rossi S;Ashe MP;Portela P
• 通讯作者: Portela P