Amino acid metabolites that regulate G protein signaling during osmotic stress

• Published in: PLoS genetics Vol. 13; no. 5; p. e1006829
• Main Authors: Shellhammer, James P, Morin-Kensicki, Elizabeth, Matson, Jacob P, Yin, Guowei, Isom, Daniel G, Campbell, Sharon L, Mohney, Robert P, Dohlman, Henrik G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.05.2017; Public Library of Science (PLoS)
• Subjects: Adaptation; Amino acid metabolism; Amino acids; Amino Acids - metabolism; Analysis; Biology and Life Sciences; Care and treatment; Chain branching; Derivatives; Enzymes; G protein-coupled receptors; G proteins; Gene Expression Regulation, Fungal; GTP-Binding Protein alpha Subunits - genetics; GTP-Binding Protein alpha Subunits - metabolism; Guanine nucleotide-binding protein; Health aspects; Hog1 protein; Hypertension; Influence; Ischemia; Kinases; MAP kinase; Mass spectrometry; Mass spectroscopy; Metabolites; Metabolome; Metabolomics; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Osmosis; Osmotic Pressure; Osmotic stress; Phosphorylation; Reperfusion; Rodents; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Second messengers; Services; Signal Transduction; Transcription; Yeast; United States; North Carolina; United States > US
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006829

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.