Amino acid metabolites that regulate G protein signaling during osmotic stress

Creator

Shellhammer, James P.
- Affiliation: School of Medicine, Department of Pharmacology
Morin-Kensicki, Elizabeth
- Other Affiliation: Metabolon; Inc
Matson, Jacob P.
- Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Yin, Guowei
- ORCID: 0000-0003-2669-7160
- Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Isom, Daniel G.
- Other Affiliation: The University of Miami Miller School of Medicine
Campbell, Sharon L.
- Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Mohney, Robert P.
- Other Affiliation: Metabolon; Inc
Dohlman, Henrik G.
- Affiliation: School of Medicine, Department of Pharmacology
- Other Affiliation: Department of Biochemistry and Biophysics

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.

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