Abstract
All cells respond to osmotic stress by implementing molecular signaling events to protect the organism. Failure to properly adapt can lead to pathologies such as hypertension and ischemia-reperfusion injury. Mitogen-activated protein kinases (MAPKs) are activated in response to osmotic stress, as well as by signals acting through G protein-coupled receptors (GPCRs). For proper adaptation, the action of these kinases must be coordinated. To identify second messengers of stress adaptation, we conducted a mass spectrometry-based global metabolomics profiling analysis, quantifying nearly 300 metabolites in the yeast S. cerevisiae. We show that three branched-chain amino acid (BCAA) metabolites increase in response to osmotic stress and require the MAPK Hog1. Ectopic addition of these BCAA derivatives promotes phosphorylation of the G protein α subunit and dampens G protein-dependent transcription, similar to that seen in response to osmotic stress. Conversely, genetic ablation of Hog1 activity or the BCAA-regulatory enzymes leads to diminished phosphorylation of Gα and increased transcription. Taken together, our results define a new class of candidate second messengers that mediate cross talk between osmotic stress and GPCR signaling pathways.
Highlights
Cells routinely experience changing and often unfavorable conditions in their environment
Many are transmitted by G protein-coupled receptors (GPCRs) or the high osmolarity glycerol (HOG) pathway
We find that three branched-chain amino acid (BCAA) metabolites increase in response to osmotic stress and require the stress response Mitogen-activated protein kinases (MAPKs) Hog1
Summary
Cells routinely experience changing and often unfavorable conditions in their environment. The ability to adapt to environmental stress and re-establish homeostasis is essential to the survival of a cell, and to the well-being of the organism The response to such physical or chemical stresses is mediated by well-defined signaling networks. Changes in nutrient availability switch signaling between the opposing target of rapamycin (TOR) and AMP-activated protein kinase (AMPK) pathways [1, 2]. Stressors such as UV irradiation, inflammatory cytokines, and osmotic shock promote signaling through activation of the p38 and c-Jun N-terminal Kinase (JNK) MAPK pathways [3, 4]. We investigate cross-talk between osmotic stress and G protein-coupled receptor (GPCR) signaling pathways
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