title: p33 (gC1q receptor) prevents cell damage by blocking the cytolytic activity of antimicrobial peptides.
abstract: The innate immune system is the first line of defense against invading microbes. Its specificity relies a great deal on host pattern recognition molecules that sense pathogen-associated molecular patterns of the invading pathogen. However, full protection is not always guaranteed, and some early defense mechanisms involved in bacterial killing, such as the complement system, can also exert cytolytic activity against host cells. Although these cascades are tightly regulated, the host has to take additional precautions to prevent its cell destruction. In this study, we describe that p33, a negatively charged surface protein found on endothelial cells also known as gC1q receptor, protects host cells from a cytolytic attack by antimicrobial peptides (AMPs), such as LL37 and β-defensin 3. To this end, we characterized the interaction of p33 with AMPs by biochemical and functional means. Our data show that p33 forms a doughnut-shaped trimer that can bind up to three AMPs, and we identified a segment in p33 forming a β-sheet that mediates the binding to all AMPs. Moreover, our results show that p33 abolishes the lytic activity of AMPs at an equimolar ratio, and it protects endothelial cells and erythrocytes from AMP-induced lysis. Taken together, our data suggest a novel protective mechanism of p33 in modulating innate immune response by neutralizing cytotoxic AMPs at the host cell surface.
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Lund University, Tornavägen 10, SE-22184 Lund, Sweden.
authors.forename: Johannes
authors.initials: J
authors.lastname: Westman
authors.forename: Finja C
authors.initials: FC
authors.lastname: Hansen
authors.forename: Anders I
authors.initials: AI
authors.lastname: Olin
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides; D001665:Binding Sites; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D054804:Cathelicidins / Q000494:pharmacology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D024101:Mitochondrial Proteins / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D023083:beta-Defensins / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; C087299:C1QBP protein, human; D002352:Carrier Proteins; D054804:Cathelicidins; C422950:DEFB103A protein, human; D024101:Mitochondrial Proteins; D023083:beta-Defensins