title: The AgrD N-terminal leader peptide of Staphylococcus aureus has cytolytic and amyloidogenic properties.
abstract: Staphylococcus aureus virulence is coordinated through the Agr quorum-sensing system to produce an array of secreted molecules. One important class of secreted virulence factors is the phenol-soluble modulins (PSMs). PSMs are small-peptide toxins that have recently been characterized for their roles in infection, biofilm development, and subversion of the host immune system. In this work, we demonstrate that the signal peptide of the S. aureus quorum-sensing signal, AgrD, shares structural and functional similarities with the PSM family of toxins. The efficacy of this peptide (termed N-AgrD) beyond AgrD propeptide trafficking has never been described before. We observe that N-AgrD, like the PSMs, is found in the amyloid fibrils of S. aureus biofilms and is capable of forming and seeding amyloid fibrils in vitro. N-AgrD displays cytolytic and proinflammatory properties that are abrogated after fibril formation. These data suggest that the N-AgrD leader peptide affects S. aureus biology in a manner similar to that described previously for the PSM peptide toxins. Taken together, our findings suggest that peptide cleavage products can affect cellular function beyond their canonical roles and may represent a class of virulence factors warranting further exploration.
authors: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Kelly
authors: K
authors: Schwartz
authors: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Matthew D
authors: MD
authors: Sekedat
authors: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Adnan K
authors: AK
authors: Syed
authors: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Brendan
authors: B
authors: O'Hara
authors: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors: David E
authors: DE
authors: Payne
authors: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Abigail
authors: A
authors: Lamb
authors: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA blaise-boles@uiowa.edu.
authors: Blaise R
authors: BR
authors: Boles
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D018441:Biofilms / Q000254:growth & development; D006801:Humans; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology; D010456:Peptides, Cyclic / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics; D053038:Quorum Sensing / Q000235:genetics; D013203:Staphylococcal Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism*; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C414532:AgrD protein, Staphylococcus; D000682:Amyloid; D001426:Bacterial Proteins; D010456:Peptides, Cyclic; D021382:Protein Sorting Signals; D037521:Virulence Factors