Alterations of the Saccharomyces cerevisiae proteome by protein production are dependent on strain origins

Abstract Saccharomyces cerevisiae yeast is a widely used recombinant protein production host. Recombinant protein expression requires adaptation of the host cell proteome to accommodate the increased biosynthetic and folding demands. However, this underlying proteomic changes remain poorly understood. In this study, we quantified the proteome of a laboratory S. cerevisiae strain over four days during batch cultivation for recombinant laccase production to characterize the resulting proteomics remodeling. Whereas a substantial portion of the proteome changed in response to nutrient depletion during batch growth, only a smaller subset of proteins was affected by laccase expression. By comparing yeast strains of different origins and laccase production capacities, we found that each strain displayed a distinct response to heterologous expression, regardless of the origin of the laccase. For example, the chaperones Hsp26 and Kar2 were specifically elevated in a whey-derived strain upon laccase expression. Nonetheless, the higher capacity to produce active recombinant laccase in some strains appears to be associated primarily with small groups of proteins that are constitutively expressed at different levels. These results indicate that strains of different origins each provide a unique cellular milieu that, in some cases, is more favorable for the expression of a given recombinant protein. This study provides the first insights into the dynamic proteome remodeling that occurs during recombinant laccase expression and highlights the potential of exploiting naturally occurring yeast diversity, rather than relying solely on strain engineering, to improve recombinant protein yields. Key points • Proteomes of S. cerevisiae strains during recombinant laccase expression determined • Ribosomal and metabolic protein levels change during recombinant expression • Unique cellular milieu, rather than proteome shifts, is linked to higher yields