Abstract
Hosts used for the production of recombinant proteins are typically high-protein secreting mutant strains that have been selected for a specific purpose, such as efficient production of cellulose-degrading enzymes. Somewhat surprisingly, sequencing of the genomes of a series of mutant strains of the cellulolytic Trichoderma reesei, widely used as an expression host for recombinant gene products, has shed very little light on the nature of changes that boost high-level protein secretion. While it is generally agreed and shown that protein secretion in filamentous fungi occurs mainly through the hyphal tip, there is growing evidence that secretion of proteins also takes place in sub-apical regions. Attempts to increase correct folding and thereby the yields of heterologous proteins in fungal hosts by co-expression of cellular chaperones and foldases have resulted in variable success; underlying reasons have been explored mainly at the transcriptional level. The observed physiological changes in fungal strains experiencing increasing stress through protein overexpression under strong gene promoters also reflect the challenge the host organisms are experiencing. It is evident, that as with other eukaryotes, fungal endoplasmic reticulum is a highly dynamic structure. Considering the above, there is an emerging body of work exploring the use of weaker expression promoters to avoid undue stress. Filamentous fungi have been hailed as candidates for the production of pharmaceutically relevant proteins for therapeutic use. One of the biggest challenges in terms of fungally produced heterologous gene products is their mode of glycosylation; fungi lack the functionally important terminal sialylation of the glycans that occurs in mammalian cells. Finally, exploration of the metabolic pathways and fluxes together with the development of sophisticated fermentation protocols may result in new strategies to produce recombinant proteins in filamentous fungi.
Highlights
As scavengers of recalcitrant polymers in nature, filamentous fungi such as the cellulolytic Trichoderma reesei are exceptionally good secretors of proteins outside the growing hyphae
Protein secretion provides a platform for the eukaryotic style post-translational modification of proteins
In order to capitalize on METABOLIC ENGINEERING AND SYNTHETIC BIOLOGY Metabolic engineering and the application of synthetic biology are heavily reliant on the breadth and depth of large-scale
Summary
As scavengers of recalcitrant polymers in nature, filamentous fungi such as the cellulolytic Trichoderma reesei are exceptionally good secretors of proteins outside the growing hyphae. As these levels are far better than with any other organism, filamentous fungi hold the promise for an ultimate production host for recombinant proteins on an industrial scale Toward this end, current research is carried out into cellular mechanisms for internal protein quality control, secretion stress, functional genomics relating to protein expression and secretion, post-translational protein modification, application of alternative expression promoters, identification of specific transcription factors and linking the fungal physiology to productivity (reviewed in Punt et al, 2002; Meyer, 2008; Lubertozzi and Keasling, 2009; Sharma et al, 2009; Fleissner and Dersch, 2010; Schuster and Schmoll, 2010; Ward, 2012).
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