HOG Signaling: A Multifunctional Regulator of Stress Homeostasis in Saccharomyces cerevisiae.

During growth and metabolism, the budding yeast Saccharomyces cerevisiae is continuously exposed to diverse environmental stresses, and conserved mitogen-activated protein kinase (MAPK) cascades execute core functions in stress sensing and adaptive regulation. The high-osmolarity glycerol (HOG) pathway, a classical MAPK cascade in S. cerevisiae, was initially identified as the core regulator of hyperosmotic stress responses. Over recent decades, accumulating evidence has revealed that the HOG pathway is not merely an osmoregulatory module but a versatile signaling hub that integrates multiple stress inputs and orchestrates a broad spectrum of adaptive responses. This review systematically summarizes the core architecture of the HOG pathway, including its upstream sensing branches (Sln1 and Sho1) and the conserved three-tiered MAPK cascade, with an emphasis on how different stressors engage distinct branches and lead to differential Hog1 phosphorylation kinetics. This review further discusses the multifaceted roles of the HOG pathway in stress adaptation, covering transcriptional reprogramming, cell cycle arrest, metabolic reprogramming centered on glycerol synthesis, and emerging functions such as cell wall remodeling, flocculation, mitophagy, and cross-talk with other MAPK pathways. By integrating classical and contemporary findings, this review presents a comprehensive view of the HOG pathway in S. cerevisiae and provides a reference for future research on stress signaling and engineering of this model organism.