Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 21, Issue 3, Pages 414-437Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2014.5844
Keywords
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Funding
- Austrian Science Fund (FWF)
- Austrian Research Promotion Agency
- European Science Foundation (ESF)
- Federal Ministry of Economy, Family, and Youth (BMWFJ)
- Federal Ministry of Traffic, Innovation, and Technology (bmvit)
- Styrian Business Promotion Agency SFG
- Standortagentur Tirol and ZIT-Technology Agency of the City of Vienna through the COMET-Funding Program
- Polymun Scientific GmbH
- Biomin Research Center
- Boehringer-Ingelheim RCV
- Lonza AG
- Biocrates Life Sciences AG
- VTU Technology GmbH
- Sandoz GmbH
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Significance: Recombinant protein production has developed into a huge market with enormous positive implications for human health and for the future direction of a biobased economy. Limitations in the economic and technical feasibility of production processes are often related to bottlenecks of in vivo protein folding. Recent Advances: Based on cell biological knowledge, some major bottlenecks have been overcome by the overexpression of molecular chaperones and other folding related proteins, or by the deletion of deleterious pathways that may lead to misfolding, mistargeting, or degradation. Critical Issues: While important success could be achieved by this strategy, the list of reported unsuccessful cases is disappointingly long and obviously dependent on the recombinant protein to be produced. Singular engineering of protein folding steps may not lead to desired results if the pathway suffers from several limitations. In particular, the connection between folding quality control and proteolytic degradation needs further attention. Future Directions: Based on recent understanding that multiple steps in the folding and secretion pathways limit productivity, synergistic combinations of the cell engineering approaches mentioned earlier need to be explored. In addition, systems biology-based whole cell analysis that also takes energy and redox metabolism into consideration will broaden the knowledge base for future rational engineering strategies.
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