Phosphoproteomics of WHO-Priority Fungal Pathogens: Conserved Signaling Architecture, Pathogen-Specific Outputs, and Therapeutic Vulnerabilities.

Protein phosphorylation is a central post-translational modification. In pathogenic fungi, it dynamically governs morphogenesis, stress adaptation, and antifungal drug resistance. Using high-resolution mass spectrometry-based phosphoproteomics, researchers have systematically mapped phosphorylation dynamics in WHO-priority pathogens-Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and the multidrug-resistant Candidozyma auris (formerly Candida auris). These studies reveal that thousands of phosphorylation events are coordinately reprogrammed in response to antifungal drug exposure, host-derived oxidative stress, and temperature shifts. Integration of available datasets suggests a "conserved-core/divergent-output" organization. Shared kinase hubs like cAMP-PKA, HOG-MAPK and calcineurin are broadly conserved across species. Downstream substrate networks, however, have diverged, producing distinct virulence outputs in each pathogen. Notably, C. auris remains completely uncharacterized at the phosphoproteomic level. This review provides a comprehensive synthesis of the phosphoproteomic landscape across these pathogens, and discusses how phosphoproteomic data are guiding the rational prioritization of kinases and phosphatases as next-generation antifungal drug targets-with direct implications for clinical surveillance and public health.