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<p>Gim3 is an evolutionarily conserved component of the prefoldin chaperone complex, involved in protein folding. We previously found that <i>GIM3</i> genetically interacts with many de novo mutations in <i>Saccharomyces cerevisiae</i>. Removing <i>GIM3</i> from mutagenized <i>S. cerevisiae</i> cells significantly affected the fitness effect of mutations. This indicates that Gim3 might change the evolutionary impact of de novo mutations by either buffering (hiding) or potentiating (increasing) their phenotypic effects, depending on the environmental or genetic context. Here, we investigated Gim3’s role in shaping the evolutionary fate of de novo mutations under fluconazole stress, an antifungal drug used to combat fungal infections. Applying both strong and moderate fluconazole stress in the presence or absence of <i>GIM3</i> revealed that Gim3 potentiates fluconazole susceptibility (resistance and tolerance) by enabling mutations to have immediate phenotypic effects. Deleting <i>GIM3</i> reduced growth in fluconazole in most mutants, indicating that <i>GIM3</i> could be a promising target for new antifungal therapies against drug-resistant infections. Importantly, Gim3 also modulates fluconazole susceptibility of the fungal pathogen <i>Nakaseomyces glabratus</i>, further highlighting Gim3’s role in fluconazole resistance and tolerance.</p>

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Gim3 buffers and potentiates de novo mutations that affect fluconazole susceptibility in yeast

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月17日

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  • Mohammed T Tawfeeq,
  • Dimitrios Konstantinidis,
  • Ana Lucia Rocha Iraizos,
  • Wouter Van Genechten,
  • Jolien Vreys,
  • Lieselotte Vermeersch,
  • Karin Voordeckers,
  • Patrick Van Dijck,
  • Kevin J Verstrepen

摘要

Gim3 is an evolutionarily conserved component of the prefoldin chaperone complex, involved in protein folding. We previously found that GIM3 genetically interacts with many de novo mutations in Saccharomyces cerevisiae. Removing GIM3 from mutagenized S. cerevisiae cells significantly affected the fitness effect of mutations. This indicates that Gim3 might change the evolutionary impact of de novo mutations by either buffering (hiding) or potentiating (increasing) their phenotypic effects, depending on the environmental or genetic context. Here, we investigated Gim3’s role in shaping the evolutionary fate of de novo mutations under fluconazole stress, an antifungal drug used to combat fungal infections. Applying both strong and moderate fluconazole stress in the presence or absence of GIM3 revealed that Gim3 potentiates fluconazole susceptibility (resistance and tolerance) by enabling mutations to have immediate phenotypic effects. Deleting GIM3 reduced growth in fluconazole in most mutants, indicating that GIM3 could be a promising target for new antifungal therapies against drug-resistant infections. Importantly, Gim3 also modulates fluconazole susceptibility of the fungal pathogen Nakaseomyces glabratus, further highlighting Gim3’s role in fluconazole resistance and tolerance.