The ClpCP complex modulates respiratory metabolism in Staphylococcus aureus and is regulated in a SrrAB-dependent manner.

The staphylococcal respiratory regulator (SrrAB) modulates energy metabolism in Staphylococcus aureus . Studies have suggested that regulated protein catabolism facilitates energy homeostasis. Regulated proteolysis in S. aureus is achieved through protein complexes composed of a peptidase (ClpQ or ClpP) in association with an AAA+ family ATPase (typically ClpC or ClpX). In the current report, we tested the hypothesis that SrrAB regulates a Clp complex to facilitate energy homeostasis in S. aureus . Strains deficient in one or more Clp complexes are attenuated for growth in the presence of puromycin, which causes enrichment of misfolded proteins. A Δ srrAB strain had increased sensitivity to puromycin. Epistasis experiments suggested that the puromycin sensitivity phenotype of the Δ srrAB strain was a result of decreased ClpC activity. Consistent with this, transcriptional activity of clpC was decreased in the Δ srrAB mutant and overexpression of clpC suppressed the puromycin sensitivity of the Δ srrAB strain. We also found that ClpC positively influenced respiration and it does so upon association with ClpP. In contrast, ClpC limits fermentative growth while ClpP was required for optimal fermentative growth. Metabolomics studies demonstrated that intracellular metabolic profiles of the Δ clpC and Δ srrAB mutants are distinct from the wild type strain, supporting the notion that both ClpC and SrrAB affect central metabolism. We propose a model wherein SrrAB regulates energy homeostasis, in part, via modulation of regulated proteolysis. Importance. Oxygen is used as a substrate to derive energy by the bacterial pathogen Staphylococcus aureus during infection; however, S. aureus can also grow fermentatively in the absence of oxygen. To successfully cause infection, S. aureus must tailor its metabolism to take advantage of respiratory activity. Different proteins are required for growth in the presence or absence of oxygen; therefore, when cells transition between these conditions several proteins would be expected to become unnecessary. In this report, we show that regulated proteolysis is used to modulate energy metabolism in S. aureus . We report that the ClpCP protein complex is involved in specifically modulating aerobic respiratory growth but is dispensable for fermentative growth.