The Major Autolysin Atl Regulates the Virulence of Staphylococcus aureus by Controlling the Sorting of LukAB

Infections caused by the Gram-positive bacterium Staphylococcus aureus remain a significant health threat globally. The production of bicomponent pore-forming leukocidins plays an important role in S. aureus pathogenesis. Transcriptionally, these toxins are primarily regulated by the Sae and Agr regulatory systems. However, the posttranslational regulation of these toxins is largely unexplored. In particular, one of the leukocidins, LukAB, has been shown to be both secreted into the extracellular milieu and associated with the bacterial cell envelope. Here, we report that a major cell wall hydrolase, autolysin (Atl), controls the sorting of LukAB from the cell envelope to the extracellular milieu, an effect independent of transcriptional regulation. By influencing the sorting of LukAB, Atl modulates S. aureus cytotoxicity toward primary human neutrophils. Mechanistically, we found that the reduction in peptidoglycan cleavage and increased LukAB secretion in the atl mutant can be reversed through the supplementation of exogenous mutanolysin. Altogether, our study revealed that the cell wall hydrolase activity of Atl and the cleavage of peptidoglycan play an important role in controlling the sorting of S. aureus toxins during secretion.