The C-terminal sequence of several human serine proteases encodes host defense functions

J Innate Immun. 2011;3(5):471-82. doi: 10.1159/000327016. Epub 2011 May 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Sequence
  • Animals
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / immunology
  • Antimicrobial Cationic Peptides / metabolism*
  • Cell Line
  • Disease Models, Animal
  • Humans
  • Immunity, Innate
  • Immunomodulation
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Phylogeny
  • Quantitative Structure-Activity Relationship
  • Serine Proteases / chemistry
  • Serine Proteases / genetics
  • Serine Proteases / immunology
  • Serine Proteases / metabolism*
  • Shock, Septic / chemically induced
  • Shock, Septic / immunology
  • Shock, Septic / metabolism*
  • Structural Homology, Protein

Substances

  • Antimicrobial Cationic Peptides
  • Lipopolysaccharides
  • Peptide Fragments
  • Serine Proteases