Regulation of the Sae Two-Component System by Branched-Chain Fatty Acids in Staphylococcus aureus
Augustus Pendleton, Won‐Sik Yeo, Shahad Alqahtani, Dennis A. DiMaggio, Carl J. Stone, Zhaotao Li, Vineet K. Singh, Christopher P. Montgomery, Taeok Bae, Shaun R. Brinsmade
Abstract
Two-component systems (TCSs) are an essential way that bacteria sense and respond to their environment. These systems are usually composed of a membrane-bound histidine kinase that phosphorylates a cytoplasmic response regulator. Because most of the histidine kinases are embedded in the membrane, lipids can allosterically regulate the activity of these sensors. In this study, we reveal that branched-chain fatty acids (BCFAs) are required for the activation of multiple TCSs in Staphylococcus aureus. Using both genetic and biochemical data, we show that the activity of the virulence activator SaeS and the phosphorylation of its response regulator SaeR are reduced in a branched-chain keto-acid dehydrogenase complex mutant and that defects in BCFA synthesis have far-reaching consequences for exotoxin secretion and virulence. Finally, we show that mutation of the global nutritional regulator CodY alters BCFA content in the membrane, revealing a potential mechanism of posttranscriptional regulation of the Sae system by CodY.