Metabolic excretion associated with nutrient-growth dysregulation promotes the rapid evolution of an overt metabolic defect

In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by...

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Bibliographic Details
Published in:	PLoS biology Vol. 18; no. 8; p. e3000757
Main Authors:	Green, Robin, Sonal, Wang, Lin, Hart, Samuel F M, Lu, Wenyun, Skelding, David, Burton, Justin C, Mi, Hanbing, Capel, Aric, Chen, Hung Alex, Lin, Aaron, Subramaniam, Arvind R, Rabinowitz, Joshua D, Shou, Wenying
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 24-08-2020 Public Library of Science (PLoS)
Subjects:	Adaptation, Physiological - genetics Autophagy Autophagy - drug effects Autophagy - genetics Auxotrophy Biological Evolution Biology and Life Sciences Cancer Carbon Cell cycle Cell death Cell division Cell growth Cell metabolism Cells Eukaryotes Eukaryotic cells Evolution Frequency dependence Funding Genes Genomics Glucose Glucose - metabolism Glucose - pharmacology Glutathione Growth Kinases Lysine Lysine - deficiency Lysine - pharmacology Medical research Metabolic Networks and Pathways - drug effects Metabolic Networks and Pathways - genetics Metabolism Metabolites Nitrogen Nitrogen - metabolism Nitrogen - pharmacology Nutrient availability Nutrient release Nutrients Nutrients - metabolism Nutrients - pharmacology Observations Phagocytosis Physical Sciences Physiological aspects Proteins Research and Analysis Methods Respiration Ribosomes - drug effects Ribosomes - metabolism Saccharomyces cerevisiae - drug effects Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - growth & development Saccharomyces cerevisiae - metabolism Sirolimus - pharmacology Stress, Physiological Sulfur Yeast Yeasts United States United States > US New Jersey
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Summary:	In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation ("nutrient-growth dysregulation") can lead to rapid cell death. Here, we demonstrate that cells can adapt to nutrient-growth dysregulation by evolving major metabolic defects. Specifically, when yeast lysine-auxotrophic mutant lys- encountered lysine limitation, an evolutionarily novel stress, cells suffered nutrient-growth dysregulation. A subpopulation repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly reduced glutathione (GSH) and GSH conjugates, were released by lys- cells during lysine limitation when growth was dysregulated, but not during glucose limitation when growth was regulated. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program, including autophagy. Thus, nutrient-growth dysregulation is associated with rapid organosulfur release, which enables the selection of organosulfur auxotrophy to better tune cell growth to the metabolic environment. We speculate that evolutionarily novel stresses can trigger atypical release of certain metabolites, setting the stage for the evolution of new ecological interactions.
Bibliography:	new_version The authors have declared that no competing interests exist.
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.3000757