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Ligand modulation of the Integrated stress response

综合应激反应的配体调节

基本信息

批准号：
BB/S014667/1
负责人：
Graham Pavitt
金额：
$ 54.66万
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：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS014667%2F1
关键词：
Ligand modulation Integrated stress response

项目摘要

Proteins perform nearly all functions in cells needed for life. Each protein is made from amino acids linked in chains and which folded into unique structures that enable each protein to fulfil individual roles in the body. The instructions required to make each protein correctly are determined by the DNA sequences of our genes in the genome. Called protein synthesis, it is critical that the instructions are decoded accurately at the right place and the right time. This enables organ and cell-specific proteins to only be made in those tissues and cells where they are required. It is also important that cells can both control and rapidly change which proteins they make at any one time, so that organisms can respond rapidly to changes around them. Examples include: 1) changes in protein synthesis in brain cells help to form memories; 2) during early pregnancy to ensure that embryos develop the right tissues in the right places; 3) when people are infected with viruses; and 4) when people suffer from diseases such as obesity or cancer.Protein synthesis occurs within relatively large and complex molecular machines called ribosomes that decode instructions relayed from the genome. This is made possible by the action of 'helpers' called protein synthesis factors and adapters called transfer RNAs (tRNAs). Together they bring the necessary amino acids together with gene instructions to ensure the correct proteins are made at the right time and place. This proposal concerns how protein synthesis is regulated by stress in a process widely called the integrated stress response (ISR). The protein synthesis factor called eIF2 brings the starting tRNA (tRNAi) to the ribosome to begin making every protein. eIF2 is known to be controlled by the ISR. When this control is out of balance it can contribute to common diseases such as cancers, diabetes, heart disease and a range of neurodegenerative conditions. We know the central element of the ISR is a reaction by which eIF2 can be modified response to stress by protein enzymes called protein kinases and that the modified version is switched off. A second enzyme called a phosphatase can switch eIF2 back on again to reset the control switch. So while it appears we understand this regulatory circuit, we now know that eIF2 interacts with many other protein synthesis factors rather than being found free in cells. How the regulatory kinases and phosphatases can access eIF2 when it is also interacting with these different other proteins is not known. Understanding this will inform how rapidly eIF2 can be switched between 'on' and 'off' states and identify which forms of eIF2 are resistant to change. Current models of how this works assume only free eIF2 can be modified. Our preliminary data questions this assumption and provides a strong basis to evaluate which forms of eIF2 can be regulated. We propose here a series of biochemical experiments to address which eIF2-containing complexes can be switched on and off in the ISR. The knowledge gained in understanding these reactions and interactions could help explain different responses to stress in different tissues and may help inform the design of better therapeutics for a wide range of conditions.

蛋白质在细胞中执行生命所需的几乎所有功能。每种蛋白质都是由氨基酸链连接而成，并折叠成独特的结构，使每种蛋白质在体内发挥各自的作用。正确制造每种蛋白质所需的指令是由我们基因组中基因的DNA序列决定的。被称为蛋白质合成，在正确的地点和正确的时间准确解码指令是至关重要的。这使得器官和细胞特异性蛋白质只能在需要它们的组织和细胞中产生。同样重要的是，细胞可以控制和快速改变它们在任何时候制造的蛋白质，这样生物体就可以对周围的变化做出快速反应。例子包括：1)脑细胞中蛋白质合成的变化有助于形成记忆；2)在怀孕早期，确保胚胎在正确的地方发育正确的组织；3)当人感染病毒时；4)当人们患有肥胖或癌症等疾病时。蛋白质合成发生在被称为核糖体的相对较大和复杂的分子机器中，核糖体解码来自基因组的指令。这是通过称为蛋白质合成因子的“助手”和称为转移rna （tRNAs）的“适配器”的作用而实现的。它们将必需的氨基酸与基因指令结合在一起，以确保在正确的时间和地点合成正确的蛋白质。这一建议涉及蛋白质合成如何在一个被广泛称为综合应激反应（ISR）的过程中受到应激的调节。蛋白质合成因子eIF2将起始tRNA （tRNAi）带到核糖体，开始制造每种蛋白质。已知eIF2是由ISR控制的。当这种控制失去平衡时，就会导致癌症、糖尿病、心脏病和一系列神经退行性疾病等常见疾病。我们知道ISR的核心要素是eIF2可以被一种叫做蛋白激酶的蛋白质酶修改以应对压力的反应，修改后的版本被关闭。另一种被称为磷酸酶的酶可以重新启动eIF2，从而重置控制开关。因此，虽然我们似乎理解了这种调节回路，但我们现在知道eIF2与许多其他蛋白质合成因子相互作用，而不是在细胞中发现自由。当eIF2与这些不同的其他蛋白相互作用时，调控激酶和磷酸酶是如何进入eIF2的尚不清楚。了解这一点将告知eIF2在“开”和“关”状态之间切换的速度有多快，并确定哪些形式的eIF2对变化有抵抗力。目前的工作原理模型假设只有自由的eIF2可以被修改。我们的初步数据质疑了这一假设，并为评估哪些形式的eIF2可以调节提供了强有力的基础。我们在这里提出了一系列的生化实验，以解决哪些含eif2的复合物可以在ISR中打开和关闭。在理解这些反应和相互作用中获得的知识可以帮助解释不同组织对压力的不同反应，并可能有助于为各种情况设计更好的治疗方法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.

DOI：
10.1038/s41467-021-21053-2
发表时间：
2021-02-05
期刊：
Nature communications
影响因子：
16.6
作者：
Faundes V;Jennings MD;Crilly S;Legraie S;Withers SE;Cuvertino S;Davies SJ;Douglas AGL;Fry AE;Harrison V;Amiel J;Lehalle D;Newman WG;Newkirk P;Ranells J;Splitt M;Cross LA;Saunders CJ;Sullivan BR;Granadillo JL;Gordon CT;Kasher PR;Pavitt GD;Banka S
通讯作者：
Banka S

Overlapping regions of Caf20 mediate its interactions with the mRNA-5'cap-binding protein eIF4E and with ribosomes.

DOI：
10.1038/s41598-021-92931-4
发表时间：
2021-06-29
期刊：
Scientific reports
影响因子：
4.6
作者：
Nwokoye EC;AlNaseem E;Crawford RA;Castelli LM;Jennings MD;Kershaw CJ;Pavitt GD
通讯作者：
Pavitt GD

GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity.