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

## TL;DR

Gim3, a protein involved in folding, influences how mutations affect yeast's response to the antifungal drug fluconazole, potentially aiding drug resistance.

## Contribution

The study reveals that Gim3 potentiates or buffers de novo mutations affecting fluconazole susceptibility in yeast.

## Key findings

- Gim3 modulates the phenotypic effects of mutations in fluconazole resistance and tolerance.
- Gim3 stabilizes mutant Erg3 proteins, which affects sterol synthesis and fluconazole growth.
- Deleting GIM3 reduces fluconazole resistance in most yeast mutants.

## Abstract

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.

The prefoldin subunit Gim3 potentiates fluconazole resistance and tolerance by enabling mutations to have immediate phenotypic effects. One example is that Gim3 stabilizes mutant Erg3 sterol desaturase proteins, maintaining (altered) sterol synthesis that sustains fluconazole growth.

Gim3 modulates the phenotypic effects of mutations.GIM3-dependent fluconazole resistance and tolerance frequently involve mutations in the ERG3 gene.Gim3 contributes to stabilizing mutant Erg3 mutants.Gim3 plays a key role in fluconazole susceptibility in S. cerevisiae and N. glabrata.

Gim3 modulates the phenotypic effects of mutations.

GIM3-dependent fluconazole resistance and tolerance frequently involve mutations in the ERG3 gene.

Gim3 contributes to stabilizing mutant Erg3 mutants.

Gim3 plays a key role in fluconazole susceptibility in S. cerevisiae and N. glabrata.

The prefoldin subunit Gim3 potentiates fluconazole resistance and tolerance by enabling mutations to have immediate phenotypic effects. One example is that Gim3 stabilizes mutant Erg3 sterol desaturase proteins, maintaining (altered) sterol synthesis that sustains fluconazole growth.