Decoding the HOG pathway of the pathogenic mold Aspergillus fumigatus: Functional and spatial analysis of the multistep phosphorelay.

• Applicant: Dr. Sebastian Schrüfer
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565759656

The HOG pathway is a critical signaling cascade in yeast and filamentous fungi, and it holds potential as a drug target for novel antifungal agents. While the individual components of this signaling network are well-characterized, the initial segment - known as the multistep phosphorelay - remains poorly understood in filamentous fungi. This part of the pathway is the key element for detecting both physiological and pharmacological signals and translating them into either adaptive or lethal responses. The spatial and temporal dynamics of these proteins add another layer of complexity, making the HOG pathway even more challenging and interesting. The primary goals of this project are to investigate protein-protein interactions between the components of the multistep phosphorelay and to explore the spatial distribution of these interactions. Additionally, we aim to examine how TcsC activates the HOG pathway in response to hyperosmotic stress or fludioxonil, and whether this activation triggers a transition from kinase to phosphatase activity. Another aspect of the project will focus on comparing the kinase modules of TcsA, TcsB, and TcsC to identify the specific domains or sequences in the TcsC kinase module that are responsible for inducing lethal activity. A further subproject will aim to identify the phosphorylation sites on Skn7 and investigate how they regulate its activity. Lastly, we will explore whether SrrB plays a role as a third response regulator in the multistep phosphorelay of Aspergillus fumigatus. The various subprojects are designed to provide a significantly deeper understanding of the processes and molecules involved in the HOG pathway, which enables adaptation to diverse stress conditions and mediates the antifungal effect of fludioxonil.

• DFG Programme: Research Grants