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Applied and Environmental Microbiology, December 2008, p. 7759-7766, Vol. 74, No. 24
0099-2240/08/$08.00+0     doi:10.1128/AEM.01178-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Modulation of Chaperone Gene Expression in Mutagenized Saccharomyces cerevisiae Strains Developed for Recombinant Human Albumin Production Results in Increased Production of Multiple Heterologous Proteins{triangledown}

T. Payne,1,2* C. Finnis,1 L. R. Evans,1 D. J. Mead,1 S. V. Avery,2 D. B. Archer,2 and D. Sleep1

Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, Nottingham NG7 1FD, United Kingdom,1 School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom2

Received 27 May 2008/ Accepted 12 October 2008

The yeast Saccharomyces cerevisiae has been successfully established as a commercially viable system for the production of recombinant proteins. Manipulation of chaperone gene expression has been utilized extensively to increase recombinant protein production from S. cerevisiae, focusing predominantly on the products of the protein disulfide isomerase gene PDI1 and the hsp70 gene KAR2. Here we show that the expression of the genes SIL1, LHS1, JEM1, and SCJ1, all of which are involved in regulating the ATPase cycle of Kar2p, is increased in a proprietary yeast strain, developed by several rounds of random mutagenesis and screening for increased production of recombinant human albumin (rHA). To establish whether this expression contributes to the enhanced-production phenotype, these genes were overexpressed both individually and in combination. The resultant strains showed significantly increased shake-flask production levels of rHA, granulocyte-macrophage colony-stimulating factor, and recombinant human transferrin.

* Corresponding author. Mailing address: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, Nottingham NG7 1FD, United Kingdom. Phone: 44 (0)115 9553355. Fax: 44 (0)115 9551299. E-mail: tpay{at}novozymes.com

{triangledown} Published ahead of print on 17 October 2008.

Applied and Environmental Microbiology, December 2008, p. 7759-7766, Vol. 74, No. 24
0099-2240/08/$08.00+0     doi:10.1128/AEM.01178-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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