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Impact of oxygen availability on the organelle-specific redox potentials and stress in recombinant protein producing Komagataella phaffii

ABSTRACT: Impact of oxygen availability on the organelle-specific redox potentials and stress in recombinant protein producing Komagataella phaffii

PROVIDER: PRJNA1162479 | ENA |

REPOSITORIES: ENA

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Impact of oxygen availability on the organelle-specific redox potentials and stress in recombinant protein producing Komagataella phaffii

Project description:The yeast Komagataella phaffii (syn. Pichia pastoris) is a highly effective and well-established host for the production of recombinant proteins. The redox balance of its secretory pathway, which is multi-organelle dependent, is of high importance for producing secretory proteins. Redox imbalance and oxidative stress an significantly influence protein folding and secretion. Glutathione serves as the main redox buffer of the cell and cellular redox conditions can be assessed through the status of the glutathione redox couple (GSH-GSSG). Previous research often focused on the redox potential of the endoplasmic reticulum (ER), where oxidative protein folding and disulfide bond formation occur. In this study, in vivo measurements of the glutathione redox potential were extended to different subcellular compartments by targeting genetically encoded redox sensitive fluorescent proteins (roGFPs) to the cytosol, ER, mitochondria and peroxisomes. Using these biosensors, the impact of oxygen availability on the redox potentials of the different organelles was investigated in non-producing and producing K. phaffii strains in glucose-limited chemostat cultures. It was found that the transition from normoxic to hypoxic conditions affected the redox potentials of all investigated organelles, while the exposure to hyperoxic conditions did not impact them. Also, as reported previously, hypoxic conditions led to increased recombinant protein secretion. Finally, transcriptome and proteome analyses provided novel insights into the short-term adaptation of the cells from normoxic to hypoxic conditions.

2025-02-10 | GSE277464 | GEO

Impact of oxygen availability on the organelle-specific redox potentials and stress in recombinant protein producing Komagataella phaffii

Project description:The methylotrophic yeast Komagataella phaffii (syn. Pichia pastoris) is one of the most effective and established expression hosts for heterologous protein production. The redox balance of its secretory pathway, which is multi-organelle dependent, is of high importance for recombinant protein production. Redox imbalance and oxidative stress are two main factors that can influence protein production and secretion, especially the redox potential of the ER where protein folding and disulfide bond formation occur. Glutathione is the main redox buffer of the cell and its redox conditions can be determined by the status of the glutathione redox couple (GSH-GSSG). In this study, in vivo measurements of the glutathione redox potential in different subcellular compartments were achieved by genetically encoded redox sensitive fluorescent probes (roGFPs). Using these biosensors, the impact of oxygen availability on the redox potentials of different organelles (cytosol, ER, mitochondria and peroxisomes) of non-producing and producing K. phaffii strains in glucose-limited chemostat cultures was investigated. It was found that the transition from normoxic to hypoxic conditions affected the redox potentials of all investigated organelles. Also, as reported previously, hypoxic conditions led to increased recombinant protein secretion. Finally, transcriptome and proteome datasets analysis provided novel insights into the short-term adaptation of the cells from normoxic to hypoxic conditions. In conclusion, improved production of therapeutic disulfide-bonded proteins in industrial settings can be achieved by tuning oxidative stress and redox homeostasis in the K. phaffii strains.

2025-01-30 | PXD055501 | Pride

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