The Fungal Response Regulator Skn7: Domain Architecture and Multifunctional Roles in Fungal Biology

The two-component phosphorelay system (TCS) is an ancient signaling module that enables fungal adaptation to changing environments. It consists of a hybrid histidine kinase (HHK), a histidine phosphotransfer protein (HPt), and downstream response regulators (RRs). Among these, the nuclear response regulator Skn7 is unique to fungi and absent from mammalian and plant cells, making it an attractive antifungal target. This review integrates structural and functional evidence to describe the multi-layered regulatory architecture of Skn7 orthologs across fungal phyla. Structurally, Skn7 combines prokaryotic signaling with eukaryotic transcriptional features through a conserved receiver (REC) domain, a central coiled-coil oligomerization motif, and a winged helix-turn-helix heat shock factor (HSF) DNA-binding domain. Functionally, Skn7 coordinates oxidative stress responses through cross-talk with the osmotic and cell wall integrity (CWI) MAPK pathways while acting as both a transcriptional activator and co-repressor. Notably, Skn7 regulates fungal development, morphogenesis, secondary metabolism-including pigments, toxins, and volatile organic compounds involved in interspecific competition-and cell fate by controlling autolysis and programmed cell death cascades. Overall, this comprehensive review highlights the evolutionary plasticity and functional versatility of Skn7, supporting its potential as a therapeutic target against fungal infections.