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Identifying and overcoming protein secretion bottlenecks in yeast and filamentous fungal cell factories

识别并克服酵母和丝状真菌细胞工厂中的蛋白质分泌瓶颈

基本信息

批准号：
BB/F004389/1
负责人：
David Archer
金额：
$ 46.2万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FF004389%2F1
关键词：
Identifying overcoming protein secretion bottlenecks

项目摘要

Yeasts and moulds are both types of fungi. While yeasts such as Saccharomyces cerevisiae are widely regarded as useful because of its roles in making beer and wine, and in making bread, most moulds are regarded as a nuisance because they cause visible spoilage of foods, even though some species have uses in making valuable chemicals (e.g. penicillin). In fact, both yeasts and moulds are very important and are used commercially to make proteins that are not naturally produced by that fungus. In those cases, the gene that is necessary to make the protein is introduced into the fungus. Examples are insulin (for diabetics), chymosin (for cheese production) and a variety of enzymes used in food processing. Also, basic information about how enzymes work requires a plentiful supply of protein which usually means that those proteins are produced by a 'cell factory' such as a fungus. A common difficulty in making proteins from cell factories is that the yields are lower than desired. That is because the cell senses that it is being asked to make, and secrete to the outside of the cell, a protein which it wouldn't ordinarily make. The cell becomes stressed and it initiates a series of events within the cell aimed at protecting itself which, in so-doing, reduces the yield of protein secreted to the outside of the cell. Some proteins give rise to a bigger stress than others but we do not know the rules that govern the stress. This project aims to identify the rules and, thereby, understand how to predict which proteins will cause most stress and then to take steps with the 'cell factory' organisms to counteract the stress. In that way, we hope to be able to improve the cell factories to make more of the desired proteins. In particular, we aim to improve the capacity of fungal cell factories to produce antibody molecules that could be useful clinically.

酵母菌和霉菌都是真菌。虽然像酿酒酵母这样的酵母被广泛认为是有用的，因为它在制造啤酒和葡萄酒以及面包中的作用，但大多数霉菌被认为是一种讨厌的东西，因为它们会导致食物的可见腐败，即使有些物种可以用于制造有价值的化学品（例如青霉素）。事实上，酵母菌和霉菌都非常重要，它们在商业上被用来制造真菌天然不产生的蛋白质。在这些情况下，制造蛋白质所必需的基因被引入真菌。例如胰岛素（用于糖尿病患者），凝乳酶（用于奶酪生产）和各种用于食品加工的酶。此外，关于酶如何工作的基本信息需要大量的蛋白质供应，这通常意味着这些蛋白质是由真菌等“细胞工厂”产生的。从细胞工厂生产蛋白质的一个常见困难是产量低于预期。这是因为细胞感觉到它被要求制造，并分泌到细胞外，它通常不会制造的蛋白质。细胞变得紧张，它在细胞内启动一系列旨在保护自身的事件，这样做会减少分泌到细胞外的蛋白质的产量。有些蛋白质比其他蛋白质产生更大的压力，但我们不知道控制压力的规则。该项目旨在确定规则，从而了解如何预测哪些蛋白质将导致最大的压力，然后采取措施与“细胞工厂”生物体对抗压力。通过这种方式，我们希望能够改进细胞工厂，以制造更多所需的蛋白质。特别是，我们的目标是提高真菌细胞工厂生产可能在临床上有用的抗体分子的能力。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activation of the unfolded protein response in Pichia pastoris requires splicing of a HAC1 mRNA intron and retention of the C-terminal tail of Hac1p.

毕赤酵母中未折叠蛋白反应的激活需要 HAC1 mRNA 内含子的剪接和 Hac1p C 末端尾部的保留。

DOI：
10.1016/j.febslet.2011.02.036
发表时间：
2011
期刊：
FEBS letters
影响因子：
3.5
作者：
Whyteside G
通讯作者：
Whyteside G

A protocol for the subcellular fractionation of Saccharomyces cerevisiae using nitrogen cavitation and density gradient centrifugation.

使用氮空化和密度梯度离心对酿酒酵母进行亚细胞分级的方案。

DOI：
10.1002/yea.3002
发表时间：
2014
期刊：
Yeast (Chichester, England)
影响因子：
0
作者：
Wang Y
通讯作者：
Wang Y

Investigating the physiological response of Pichia (Komagataella) pastoris GS115 to the heterologous expression of misfolded proteins using chemostat cultures.

DOI：
10.1007/s00253-013-5186-1
发表时间：
2013-11
期刊：
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
影响因子：
5
作者：
Hesketh, Andrew R.;Castrillo, Juan I.;Sawyer, Trevor;Archer, David B.;Oliver, Stephen G.
通讯作者：
Oliver, Stephen G.

Native-state stability determines the extent of degradation relative to secretion of protein variants from Pichia pastoris.

天然状态的稳定性决定了与毕赤酵母分泌的蛋白质变体相关的降解程度。