PLoS Genetics (May 2017)

Amino acid metabolites that regulate G protein signaling during osmotic stress.

  • James P Shellhammer,
  • Elizabeth Morin-Kensicki,
  • Jacob P Matson,
  • Guowei Yin,
  • Daniel G Isom,
  • Sharon L Campbell,
  • Robert P Mohney,
  • Henrik G Dohlman

DOI
https://doi.org/10.1371/journal.pgen.1006829
Journal volume & issue
Vol. 13, no. 5
p. e1006829

Abstract

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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.