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Abstract
Staphylococcus aureus requires branched-chain amino acids (BCAAs; isoleucine, leucine, valine) for protein synthesis, branched-chain fatty acid synthesis, and environmental adaptation by responding to their availability via the global transcriptional regulator CodY. The importance of BCAAs for S. aureus physiology necessitates that it either synthesize them or scavenge them from the environment. Indeed S. aureus uses specialized transporters to scavenge BCAAs, however, its ability to synthesize them has remained conflicted by reports that it is auxotrophic for leucine and valine despite carrying an intact BCAA biosynthetic operon. In revisiting these findings, we have observed that S. aureus can engage in leucine and valine synthesis, but the level of BCAA synthesis is dependent on the BCAA it is deprived of, leading us to hypothesize that each BCAA differentially regulates the biosynthetic operon. Here we show that two mechanisms of transcriptional repression regulate the level of endogenous BCAA biosynthesis in response to specific BCAA availability. We identify a trans-acting mechanism involving isoleucine-dependent repression by the global transcriptional regulator CodY and a cis-acting leucine-responsive attenuator, uncovering how S. aureus regulates endogenous biosynthesis in response to exogenous BCAA availability. Moreover, given that isoleucine can dominate CodY-dependent regulation of BCAA biosynthesis, and that CodY is a global regulator of metabolism and virulence in S. aureus, we extend the importance of isoleucine availability for CodY-dependent regulation of other metabolic and virulence genes. These data resolve the previous conflicting observations regarding BCAA biosynthesis, and reveal the environmental signals that not only induce BCAA biosynthesis, but that could also have broader consequences on S. aureus environmental adaptation and virulence via CodY.
Highlights
Staphylococcus aureus is a serious human pathogen capable of causing infections that range from mild skin and soft tissue infections, to severe infections of the bone, muscle, heart and lung [1,2,3,4]
We show that S. aureus does produce leucine and valine, but only under certain nutritional conditions
The branched-chain amino acids (BCAAs; Ile, Leu, Val) represent an important group of nutrients for S. aureus metabolism and virulence, as they are required for synthesis of proteins and membrane branched-chain fatty acids (BCFAs), which are important for S. aureus membrane homeostasis and environmental adaptation
Summary
Staphylococcus aureus is a serious human pathogen capable of causing infections that range from mild skin and soft tissue infections, to severe infections of the bone, muscle, heart and lung [1,2,3,4]. The branched-chain amino acids (BCAAs; Ile, Leu, Val) represent an important group of nutrients for S. aureus metabolism and virulence, as they are required for synthesis of proteins and membrane branched-chain fatty acids (BCFAs), which are important for S. aureus membrane homeostasis and environmental adaptation. In addition to their nutritional importance, the BCAAs are key regulatory molecules in low GC-content Grampositive bacteria, as they are activators of the global transcriptional regulator CodY. Both BCAA biosynthesis [14,15,16,17,18] and transport [19,20,21,22] have been linked to promoting the virulence of other important pathogens in host environments
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