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The innate immune system uses Toll-like receptor (TLR) 2 to detect conserved bacterial lipoproteins of invading pathogens. The lipid anchor attaches lipoproteins to the cytoplasmic membrane and prevents their release from the bacterial cell envelope. How bacteria release lipoproteins and how these molecules reach TLR2 remain unknown. Staphylococcus aureus has been described to liberate membrane vesicles. The composition, mode of release, and relevance for microbe-host interaction of such membrane vesicles have remained ambiguous. We recently reported that S. aureus can release lipoproteins only when surfactant-like small peptides, the phenol-soluble modulins (PSMs), are expressed. Here we demonstrate that PSM peptides promote the release of membrane vesicles from the cytoplasmic membrane of S. aureus via an increase in membrane fluidity, and we provide evidence that the bacterial turgor is the driving force for vesicle budding under hypotonic osmotic conditions. Intriguingly, the majority of lipoproteins are released by S. aureus as components of membrane vesicles, and this process depends on surfactant-like molecules such as PSMs. Vesicle disruption at high detergent concentrations promotes the capacity of lipoproteins to activate TLR2. These results reveal that vesicle release by bacterium-derived surfactants is required for TLR2-mediated inflammation. IMPORTANCE Our study highlights the roles of surfactant-like molecules in bacterial inflammation with important implications for the prevention and therapy of inflammatory disorders. It describes a potential pathway for the transfer of hydrophobic bacterial lipoproteins, the major TLR2 agonists, from the cytoplasmic membrane of Gram-positive bacteria to the TLR2 receptor at the surface of host cells. Moreover, our study reveals a molecular mechanism that explains how cytoplasmic and membrane-embedded bacterial proteins can be released by bacterial cells without using any of the typical protein secretion routes, thereby contributing to our understanding of the processes used by bacteria to communicate with host organisms and the environment.

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The Mechanism behind Bacterial Lipoprotein Release: Phenol-Soluble Modulins Mediate Toll-Like Receptor 2 Activation via Extracellular Vesicle Release from Staphylococcus aureus