Abstract
Evolutionarily conserved mitogen activated protein kinase (MAPK) pathways regulate the response to stress as well as cell differentiation. In Saccharomyces cerevisiae, growth in non-preferred carbon sources (like galactose) induces differentiation to the filamentous cell type through an extracellular-signal regulated kinase (ERK)-type MAPK pathway. The filamentous growth MAPK pathway shares components with a p38-type High Osmolarity Glycerol response (HOG) pathway, which regulates the response to changes in osmolarity. To determine the extent of functional overlap between the MAPK pathways, comparative RNA sequencing was performed, which uncovered an unexpected role for the HOG pathway in regulating the response to growth in galactose. The HOG pathway was induced during growth in galactose, which required the nutrient regulatory AMP-dependent protein kinase (AMPK) Snf1p, an intact respiratory chain, and a functional tricarboxylic acid (TCA) cycle. The unfolded protein response (UPR) kinase Ire1p was also required for HOG pathway activation in this context. Thus, the filamentous growth and HOG pathways are both active during growth in galactose. The two pathways redundantly promoted growth in galactose, but paradoxically, they also inhibited each other's activities. Such cross-modulation was critical to optimize the differentiation response. The human fungal pathogen Candida albicans showed a similar regulatory circuit. Thus, an evolutionarily conserved regulatory axis links metabolic respiration and AMPK to Ire1p, which regulates a differentiation response involving the modulated activity of ERK and p38 MAPK pathways.
Highlights
Organisms sense and respond to diverse stimuli through the action of signal transduction pathways
Differentiation to the filamentous/hyphal cell type is critical for entry into host cells and virulence
Comparative RNA sequencing was used to explore the pathways that regulate differentiation to the filamentous cell type in yeast. This approach uncovered a role for the stressresponse mitogen activated protein kinase (MAPK) pathway, High Osmolarity Glycerol response (HOG), during the increased metabolic respiration that induces filamentous growth
Summary
Organisms sense and respond to diverse stimuli through the action of signal transduction pathways. During complex behaviors like cell differentiation, multiple pathways choreograph changes in the cell cycle and cell polarity to produce a new cell type. In many cases, it is not clear what pathways are involved or how different pathways collaborate to produce major changes in cellular reprogramming. We investigate the problem of cell differentiation in fungal species that differentiate to the filamentous/hyphal cell type. Filamentous growth is critical for virulence [1,2]. Identifying the pathways that regulate filamentous growth, and understanding how they function in an interconnected manner, is important for studies in eukaryotic cell differentiation and fungal pathogenesis
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