title: The C-terminal sequence of several human serine proteases encodes host defense functions.
abstract: Serine proteases of the S1 family have maintained a common structure over an evolutionary span of more than one billion years, and evolved a variety of substrate specificities and diverse biological roles, involving digestion and degradation, blood clotting, fibrinolysis and epithelial homeostasis. We here show that a wide range of C-terminal peptide sequences of serine proteases, particularly from the coagulation and kallikrein systems, share characteristics common with classical antimicrobial peptides of innate immunity. Under physiological conditions, these peptides exert antimicrobial effects as well as immunomodulatory functions by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, selected peptides are protective against lipopolysaccharide-induced shock. Moreover, these S1-derived host defense peptides exhibit helical structures upon binding to lipopolysaccharide and also permeabilize liposomes. The results uncover new and fundamental aspects on host defense functions of serine proteases present particularly in blood and epithelia, and provide tools for the identification of host defense molecules of therapeutic interest.
authors.affiliation: Division of Dermatology and Venereology, Lund University, Biomedical Center, Lund, Sweden.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Kasetty
authors.forename: Praveen
authors.initials: P
authors.lastname: Papareddy
authors.forename: Martina
authors.initials: M
authors.lastname: Kalle
authors.forename: Victoria
authors.initials: V
authors.lastname: Rydengård
authors.forename: Björn
authors.initials: B
authors.lastname: Walse
authors.forename: Bo
authors.initials: B
authors.lastname: Svensson
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010802:Phylogeny; D021281:Quantitative Structure-Activity Relationship; D057057:Serine Proteases / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D040681:Structural Homology, Protein
chemical_list: D023181:Antimicrobial Cationic Peptides; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D057057:Serine Proteases