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

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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.