Surprising regulatory plasticity for the conserved HOG pathway in diverse Saccharomyces cerevisiae strains

Abstract Mitogen-activated protein kinases (MAPKs) display remarkable regulatory plasticity across evolution, ranging from highly specialized pathways to broadly responsive global signaling hubs. In the budding yeast Saccharomyces cerevisiae, the high-osmolarity glycerol (HOG) network has served as a paradigm for largely stress-specific MAPK signaling, where the Hog1 MAPK coordinates osmoadaptation. This stands in sharp contrast to Hog1 orthologs in other fungi and humans, which respond not only to osmotic stress, but also diverse stresses including UV, heat shock, oxidative stress, and pathogen signals. Whether the relative osmospecificity of S. cerevisiae Hog1 represents an ancestral feature or lineage-specific evolution remains unclear. The majority of foundational work on S. cerevisiae HOG signaling has been performed in laboratory strains that are known to be genetic and phenotypic outliers, and we have been leveraging wild S. cerevisiae strains to understand aspects of stress signaling that may have been lost in laboratory strains. Here, we examined the phenotypic effects of hog1∆ mutations in a commonly-used laboratory S. cerevisiae strain and diverse wild strains on stress cross protection and gene expression. Our findings demonstrate an expanded role in cross-stress protection for Hog1 in wild yeast strains compared to the laboratory strain. More strikingly, we identified a large number of Hog1-dependent genes for non-osmotic stresses in the wild strains that was completely absent in the lab strain. Notably, the Hog1 regulon in wild strains responding to non-osmotic stresses is largely distinct from the canonical osmotic stress response, which we show likely occurs through non-canonical cytoplasmic functions. These findings reveal surprising within-species plasticity for the highly conserved HOG network, suggesting that evolutionary transitions between specialist to generalist stress signaling may occur with relative ease. Competing Interest Statement The authors have declared no competing interest. Footnotes Added Github link to analysis code, updated growth analysis data, and revised introduction to include more references.