Reciprocal Interactions between Membrane Bilayers and S. aureus PSM alpha 3 Cross-alpha Amyloid Fibrils Account for Species-Specific Cytotoxicity

摘要

Phenol-soluble modulin alpha 3 (PSM alpha 3) is a functional amyloid secreted by the pathogenic bacterium Staphylococcus aureus. This 22-residue peptide serves as a key virulence determinant, toxic to human cells via the formation of unique cross-a amyloid-like fibrils. We demonstrate that bilayer vesicles accelerated PSM alpha 3 fibril formation, and the fibrils, in turn, inserted deeply into bilayers mimicking mammalian cell membranes, accounting for PSM alpha 3 cellular toxicity. Importantly, a mere amphipathic helical conformation was not a sufficient determinant for membrane-activity of PSM alpha 3, pointing to the functional role of cross-alpha fibrils. In contrast to deep insertion of PSM alpha 3 into mammalian membrane bilayers, the peptide only interacted with the surface of bilayers mimicking bacterial membranes, which might be related to its lack of antibacterial activity. Together, our data provide mechanistic insight into species-specific toxicity of a key bacterial amyloid virulence factor via reciprocal interactions with membranes, and open new perspectives into amyloid-related cytotoxicity mediated by helical fibril structures. (C) 2018 Elsevier Ltd. All rights reserved.