Systematic functional profiling of WD40 proteins reveals Wcp1, a cyclophilin that links CO2/heat tolerance to acidic pH adaptation in Cryptococcus neoformans [RNA-Seq]

We systematically analysed 94 canonical WD40 proteins in Cryptococcus neoformans. Conditional expression and sporulation analyses identified 36 essential WD40 proteins, while in vitro and in vivo profiling of 103 signature-tagged deletion strains spanning 52 genes uncovered 31 pathogenicity-related WD40 proteins, including epigenetic and post-transcriptional regulators.

We highlighted Wcp1, a WD40–cyclophilin fusion required for growth at 37 °C under 5% CO₂. Both modules supported CO₂/heat tolerance and virulence. Notably, Wcp1 couples these functions to acidic pH adaptation: wcp1Δ mutants failed to grow under elevated temperature and CO₂ at acidic pH, exhibited enhanced intracellular acidification, reduced survival within macrophages and attenuated virulence in both Drosophila and murine models.