Journal
CELL SYSTEMS
Volume 11, Issue 2, Pages 121-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2020.07.005
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Funding
- NIH [R35GM124732, R01-AI-042347]
- Pew Biomedical Scholars Program
- Sloan Research Fellowship
- Searle Scholars Program
- Smith Family Award for Excellence in Biomedical Research
- NIH Pre-Doctoral training grant [T32 GM007287]
- NSF graduate research fellowship
- NSERC graduate fellowship (Canada)
- HHMI International Student Fellowship
- HHMI
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Aminoacyl-tRNA synthetases (aaRSs) serve a dual role in charging tRNAs. Their enzymatic activities both provide protein synthesis flux and reduce uncharged tRNA levels. Although uncharged tRNAs can negatively impact bacterial growth, substantial concentrations of tRNAs remain deacylated even under nutrient-rich conditions. Here, we show that tRNA charging in Bacillus subtilis is not maximized due to optimization of aaRS production during rapid growth, which prioritizes demands in protein synthesis over charging levels. The presence of uncharged tRNAs is alleviated by precisely tuned translation kinetics and the stringent response, both insensitive to aaRS overproduction but sharply responsive to underproduction, allowing for just enough aaRS production atop a fitness cliff. Notably, we find that the stringent response mitigates fitness defects at all aaRS underproduction levels even without external starvation, Thus, adherence to minimal, flux-satisfying protein production drives limited tRNA charging and provides a basis for the sensitivity and setpoints of an integrated growth-control network.
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