Cells maintain homeostasis under stress conditions by minimizing damages, maintaining structural integrity and modifying the activity of macromolecules and signaling molecules such as kinases and phosphatases. Though a comprehensive view of how stress-regulated signaling pathways regulate cell survival remains elusive, new work sheds some light.

As they report in the current issue of Nature Structural Molecular Biology, Leutert et al.1, in the laboratory group of Judith Villen, have investigated how the global signaling response to stress perturbations changes in the unicellular yeast Saccharomyces cerevisiae. The budding yeast is a valuable model organism to study eukaryotic signaling regulation at a systems level, as it expresses several signaling molecules in common with human homologs2. The authors exposed S. cerevisiae to 101 perturbations — including environmental (temperature, nitrogen source, carbon source, solute concentration, pH, redox state and metal concentration) and cellular perturbations (membrane, cytoskeleton, mitochondria, DNA/RNA, proteostasis machinery and signaling pathways) — for 5 minutes each. Importantly, they developed an ingenious strategy for proteome and phosphoproteome sample preparation and methods for sample acquisition on modern mass spectrometers, along with state-of-the-art computational approaches for data analysis and visualization. Their comprehensive work shows that 18% of the phosphoproteome is regulated in a shared or a specific perturbation-dependent manner. The authors then focused on both known and previously unknown mechanisms that regulate the kinase TOR (mTOR in Homo sapiens), which couples environmental cues to the regulation of cell growth, cell cycle progression and metabolism3,4. Overall, the authors reveal that the early signaling response to environmental perturbations tightly regulates the survival of budding yeast1.