Efficient protein production by yeast requires global tuning of metabolism

Nature Communications
Mingtao HuangJens Nielsen

Abstract

The biotech industry relies on cell factories for production of pharmaceutical proteins, of which several are among the top-selling medicines. There is, therefore, considerable interest in improving the efficiency of protein production by cell factories. Protein secretion involves numerous intracellular processes with many underlying mechanisms still remaining unclear. Here, we use RNA-seq to study the genome-wide transcriptional response to protein secretion in mutant yeast strains. We find that many cellular processes have to be attuned to support efficient protein secretion. In particular, altered energy metabolism resulting in reduced respiration and increased fermentation, as well as balancing of amino-acid biosynthesis and reduced thiamine biosynthesis seem to be particularly important. We confirm our findings by inverse engineering and physiological characterization and show that by tuning metabolism cells are able to efficiently secrete recombinant proteins. Our findings provide increased understanding of which cellular regulations and pathways are associated with efficient protein secretion.

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Citations

Mar 30, 2019·Biotechnology Journal·Jens Nielsen
Aug 21, 2018·Nucleic Acids Research·Søren D PetersenMichael K Jensen
Sep 17, 2020·Journal of Industrial Microbiology & Biotechnology·Yuankun HelianDawei Zhang
Nov 7, 2018·Proceedings of the National Academy of Sciences of the United States of America·Mingtao HuangJens Nielsen
Apr 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Guokun WangDina Petranovic
May 10, 2020·Nature Communications·Qiang DingXiulai Chen
Feb 13, 2021·Metabolic Engineering·Yina LinGuo-Qiang Chen
Jun 21, 2019·Metabolic Engineering·Pamela B Besada-Lombana, Nancy A Da Silva
May 4, 2021·Frontiers in Microbiology·Xinyi ChenHu Liu
May 14, 2021·Metabolic Engineering·Olena P IshchukDina Petranovic
Sep 7, 2021·Frontiers in Genetics·Jing LiEve Syrkin Wurtele
Jan 15, 2019·Ultrasonics Sonochemistry·Esmeralda Peña-GonzalezMariana Huerta-Jimenez

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Datasets Mentioned

BETA
ERP019558

Methods Mentioned

BETA
RNA-seq
protein folding
fluorescence microscopy
electrophoresis

Software Mentioned

GO slim mapper
Subread
Platform for Integrative Analysis of Omics ( PIANO ) R package
TopHat
Cufflinks
SGD
ImageJ
DESeq

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