Defining novel mechanisms of mRNA translational control upon cold-shock in mammalian cells

定义哺乳动物细胞冷休克时 mRNA 翻译控制的新机制

• 批准号: BB/I019790/1
• 负责人: Anne Willis
• 金额: $ 38.96万
• 依托单位: MRC Toxicology Unit
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI019790%2F1
• 关键词: Defining; novel; mechanisms; mRNA; translational

The synthesis of polypeptides that are ultimately folded and decorated with various modifications in the cell to yield a functional protein is the result of a process called mRNA translation. Protein synthesis is therefore the process by which the information in the genetic material in the cell, DNA is converted via an intermediary substrate mRNA, into proteins. Translational control allows for rapid changes in protein synthesis that permits cells and organisms to maintain cellular homeostasis and respond to various stimuli, including environmental perturbations such as temperature. Surprisingly, the control of mRNA translation and subsequent protein synthesis in mammalian cells at subphysiological temperatures (cold-shock, <37degC) and upon recovery is poorly described even though cold-shock is used in transplant medicine, heart and brain surgery, implicated in mammalian hibernation, brain plasticity and ageing, and is utilised in the biotechnology sector as a method to improve recombinant protein production. Further, the two mammalian cold-shock proteins, cold inducible RNA binding protein (CIRP) and RNA binding motif protein 3 (Rbm3) are implicated in translational control and various cancers. To our knowledge we are the only group in the UK investigating translational control in mammalian cells upon cold-shock. In earlier studies we have generated data that suggests cold specific mechanisms control mRNA translation and protein synthesis in mammalian cells upon cold-shock at 27-32degC. We intend to further our earlier studies by maintaining and extending the link between our two internationally known groups to utilise a combination of interrelated approaches to investigate our over-arching hypothesis that 'upon cold-shock in mammalian cells a coordinated response involving distinct signalling pathways is activated that results in modification of the translational apparatus and its interactions, ribosomal 40S protein subunit turnover, synthesis of mRNAs which contain features recognised by specific trans acting factors, and the synthesis of specific proteins that interact with the translational apparatus to aid mRNA translation'. These studies will further define the control of translation upon cold-shock in mammalian cells, significantly improving our understanding of protein synthesis under such conditions, potentially leading to new approaches to improve protein production from mammalian cells and treatments for heart and brain damage.

最终在细胞中折叠并修饰以产生功能性蛋白质的多肽的合成是称为mRNA翻译的过程的结果。因此，蛋白质合成是细胞中遗传物质中的信息（DNA）通过中间底物mRNA转化为蛋白质的过程。翻译控制允许蛋白质合成的快速变化，允许细胞和生物体维持细胞内稳态并对各种刺激做出反应，包括环境扰动如温度。令人惊讶的是，在亚生理温度（冷休克，<37 ℃）和恢复时哺乳动物细胞中mRNA翻译和随后蛋白质合成的控制描述得很少，尽管冷休克用于移植医学、心脏和脑外科手术，涉及哺乳动物冬眠、脑可塑性和衰老，并且在生物技术领域用作改善重组蛋白质生产的方法。此外，两种哺乳动物冷休克蛋白，冷诱导RNA结合蛋白（CIRP）和RNA结合基序蛋白3（Rbm 3）涉及翻译控制和各种癌症。据我们所知，我们是英国唯一一个研究冷休克后哺乳动物细胞翻译控制的小组。在早期的研究中，我们已经产生的数据表明，在27- 32摄氏度的冷休克后，哺乳动物细胞中的冷特异性机制控制mRNA翻译和蛋白质合成。我们打算通过保持和扩展我们两个国际知名小组之间的联系来进一步我们早期的研究，以利用相互关联的方法的组合来研究我们的过度假设，即“哺乳动物细胞在冷休克后，激活了涉及不同信号通路的协调反应，导致翻译装置及其相互作用的修饰，核糖体40 S蛋白亚基转换，合成含有被特定反式作用因子识别的特征的mRNA，以及合成与翻译装置相互作用以帮助mRNA翻译的特定蛋白质。这些研究将进一步确定哺乳动物细胞中冷休克后的翻译控制，显着提高我们对这种条件下蛋白质合成的理解，可能导致新的方法来改善哺乳动物细胞的蛋白质生产和治疗心脏和脑损伤。

项目成果

Control of translation in the cold: implications for therapeutic hypothermia.

• DOI: 10.1042/bst20150052
• 发表时间: 2015-06
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: J. Knight;A. Willis

RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3.

• DOI: 10.1016/j.cub.2017.01.047
• 发表时间: 2017-03-06
• 期刊: Current biology : CB
• 作者: Bastide A;Peretti D;Knight JR;Grosso S;Spriggs RV;Pichon X;Sbarrato T;Roobol A;Roobol J;Vito D;Bushell M;von der Haar T;Smales CM;Mallucci GR;Willis AE
• 通讯作者: Willis AE

Cooling-induced SUMOylation of EXOSC10 down-regulates ribosome biogenesis.

冷却诱导的exosc10的Sumoylation下调核糖体生物发生。

• DOI: 10.1261/rna.054411.115
• 发表时间: 2016-04
• 期刊: RNA (New York, N.Y.)
• 作者: Knight JR;Bastide A;Peretti D;Roobol A;Roobol J;Mallucci GR;Smales CM;Willis AE
• 通讯作者: Willis AE

RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration.

• DOI: 10.1038/nature14142
• 发表时间: 2015-02-12
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Peretti, Diego;Bastide, Amandine;Radford, Helois;Verity, Nicholas;Molloy, Colin;Martin, Maria Guerra;Moreno, Julie A.;Steinert, Joern R.;Smith, Tim;Dinsdale, David;Willis, Anne E.;Mallucci, Giovanna R.
• 通讯作者: Mallucci, Giovanna R.