The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance
Eliciane Cevolani Mattos, Lilian Pereira Silva, Clara Valero, Patrícia Alves de Castro, Thaila Fernanda dos Reis, Liliane Fraga Costa Ribeiro, Mark R. Marten, Rafael Silva‐Rocha, Cauã Antunes Westmann, Carlos Henrique Tomich de Paula da Silva, Carlton A. Taft, Narjes Alfuraiji, Michael Bromley, Uffe Hasbro Mortensen, J. Philipp Benz, Neil Brown, Gustavo H. Goldman
Abstract
Aspergillus fumigatus is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the Δ sakA and Δ mpkC A. fumigatus and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence.