Conserved and rewired MAPK networks in human fungal pathogens

Abstract Mitogen-activated protein kinase (MAPK) cascades are among the most ancient and evolutionarily conserved signalling modules in eukaryotes, translating extracellular cues into adaptive transcriptional and metabolic outputs through a hierarchical three-tier kinase architecture. In yeasts, these pathways control osmotic and oxidative stress adaptation, mating, morphogenesis and cell wall remodelling, while in fungal pathogens they have been adapted to support virulence-factor production, host adaptation and antifungal tolerance. Here, we summarise the current understanding of MAPK signalling in the budding model yeast Saccharomyces cerevisiae, which serves throughout as a reference template, and in four human-pathogenic fungi that span the fungal kingdom—the ascomycetous yeast Candida albicans, the emerging multidrug-resistant pathogen Candidozyma (formerly Candida) auris, the filamentous mould Aspergillus fumigatus, and the basidiomycetous yeast Cryptococcus neoformans—emphasising how a conserved kinase framework has been functionally diversified to meet species-specific demands. We focus on the MAPK signalling system of C. neoformans, which is characterised by five MAPK homologues arising from paralogue retention and pervasive pathway crosstalk. We further discuss how recent systematic genetic dissection is prompting a reassessment of MAPK redundancy and network plasticity. Finally, we consider how the divergence between fungal and host MAPK signalling defines new conceptual and therapeutic directions in medical mycology.