Actin enables the antimicrobial action of LL-37 peptide in the presence of microbial proteases

J Biol Chem. 2014 Aug 15;289(33):22926-41. doi: 10.1074/jbc.M114.579672. Epub 2014 Jun 19.

Abstract

Host defense peptides play an important host-protective role by their microcidal action, immunomodulatory functions, and tissue repair activities. Proteolysis is a common strategy of pathogens used to neutralize host defense peptides. Here, we show that actin, the most abundant structural protein in eukaryotes, binds the LL-37 host defense peptide, protects it from degradation by the proteases of Pseudomonas aeruginosa and Porphyromonas gingivalis, and enables its antimicrobial activity despite the presence of the proteases. Co-localization of LL-37 with extracellular actin was observed in necrotized regions of samples from oral lesions. Competition assays, cross-linking experiments, limited proteolysis, and mass spectrometry revealed that LL-37 binds by specific hydrophobic interactions to the His-40-Lys-50 segment of actin, located in the DNase I binding loop. The integrity of the binding site of both LL-37 and actin is a prerequisite to the binding. Our results demonstrate that actin, presumably released by dead cells and abundant in infected sites, might be utilized by the immune system to enhance spatio-temporal immunity in an attempt to arrest infection and control inflammation.

Keywords: Actin; Antimicrobial Peptide (AMP); Host Defense; Protease; Transglutaminase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins* / chemistry
  • Actins* / metabolism
  • Antimicrobial Cationic Peptides* / chemistry
  • Antimicrobial Cationic Peptides* / metabolism
  • Bacterial Proteins* / chemistry
  • Bacterial Proteins* / metabolism
  • Bacteroidaceae Infections / metabolism
  • Bacteroidaceae Infections / pathology
  • Female
  • Humans
  • Male
  • Peptide Hydrolases* / chemistry
  • Peptide Hydrolases* / metabolism
  • Porphyromonas gingivalis / enzymology*
  • Protein Structure, Secondary
  • Proteolysis
  • Pseudomonas Infections / metabolism
  • Pseudomonas Infections / pathology
  • Pseudomonas aeruginosa / enzymology*

Substances

  • Actins
  • Antimicrobial Cationic Peptides
  • Bacterial Proteins
  • CAP18 lipopolysaccharide-binding protein
  • Peptide Hydrolases