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<p>Enhancing the secretion of heterologous proteins in <i>Saccharomyces cerevisiae</i> is often hindered by endoplasmic reticulum (ER) stress and inefficiencies in intracellular trafficking. To address these limitations, we systematically evaluated 14 genetic modifications associated with the secretory pathway to improve recombinant ovalbumin (OVA) production. Deletion of <i>PAH1</i>, a negative regulator of phospholipid biosynthesis, resulted in the highest OVA secretion (5.68&#xa0;mg/L), representing a 74% improvement over the background strain—likely due to increased ER membrane biogenesis. Similarly, knockout of <i>GOS1</i>, a Golgi-to-ER SNARE protein, enhanced secretion, possibly by reducing retrograde trafficking and limiting ER retention of secretory cargo. In contrast, disruption of endosome-to-Golgi transport via <i>VPS5</i> deletion resulted in intracellular accumulation of OVA and complete secretion failure. These findings suggest that alleviating ER stress and modulating vesicular trafficking are key strategies for enhancing protein secretion in yeast, offering a functional basis for rational host strain engineering.</p>

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Alleviation of ER stress via targeted genetic engineering enhances recombinant ovalbumin secretion in Saccharomyces cerevisiae

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Eun Bi Yoon,
  • Kyoung Chan Jin,
  • Yu Jeung Lim,
  • Joong-Hyuck Auh,
  • Hyun Gyu Choi,
  • Sun-Ki Kim

摘要

Enhancing the secretion of heterologous proteins in Saccharomyces cerevisiae is often hindered by endoplasmic reticulum (ER) stress and inefficiencies in intracellular trafficking. To address these limitations, we systematically evaluated 14 genetic modifications associated with the secretory pathway to improve recombinant ovalbumin (OVA) production. Deletion of PAH1, a negative regulator of phospholipid biosynthesis, resulted in the highest OVA secretion (5.68 mg/L), representing a 74% improvement over the background strain—likely due to increased ER membrane biogenesis. Similarly, knockout of GOS1, a Golgi-to-ER SNARE protein, enhanced secretion, possibly by reducing retrograde trafficking and limiting ER retention of secretory cargo. In contrast, disruption of endosome-to-Golgi transport via VPS5 deletion resulted in intracellular accumulation of OVA and complete secretion failure. These findings suggest that alleviating ER stress and modulating vesicular trafficking are key strategies for enhancing protein secretion in yeast, offering a functional basis for rational host strain engineering.