Abstract
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.
Highlights
All organisms must coordinate growth with the availability of nutrients
Because nutrient–growth regulation is conserved across eukaryotes [1], here we investigate how cells suffering nutrient–growth dysregulation might evolve, taking advantage of the lys2Δ strain (“lys−”) of S. cerevisiae
Our work demonstrates that within tens of generations, lysine-limited lys− cells often evolved into 2 subpopulations: lys− and lys−orgS− (Fig 3 and S3 Fig). lys− cells initially adapted to lysine limitation via mutations such as ecm21, rsp5, and DISOMY14
Summary
All organisms must coordinate growth with the availability of nutrients. In eukaryotes, when nutrients are abundant, cells express growth-promoting genes and grow. GSH release rate was comparable between ancestral and evolved lys− cells in lysine-limited chemostats (S7D Fig), and organosulfur supply was uninterrupted during evolution. We tested an alternative hypothesis: unable to process sulfate in the medium but able to utilize organosulfurs released by lys−, lys−orgS− cells may respond to this organosulfur limitation as to a natural limitation, mounting stress responses including autophagy. This might in turn confer lys−orgS− a fitness advantage over nutrient–growth-dysregulated lys− cells. By helping restore nutrient–growth regulation (at least partially), organosulfur limitation confers rare lys−orgS− a frequency-dependent fitness advantage over lys− during lysine limitation (S13 Fig)
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