Antimicrobial activity of human prion protein is mediated by its N-terminal region

PLoS One. 2009 Oct 7;4(10):e7358. doi: 10.1371/journal.pone.0007358.

Abstract

Background: Cellular prion-related protein (PrP(c)) is a cell-surface protein that is ubiquitously expressed in the human body. The multifunctionality of PrP(c), and presence of an exposed cationic and heparin-binding N-terminus, a feature characterizing many antimicrobial peptides, made us hypothesize that PrP(c) could exert antimicrobial activity.

Methodology and principal findings: Intact recombinant PrP exerted antibacterial and antifungal effects at normal and low pH. Studies employing recombinant PrP and N- and C-terminally truncated variants, as well as overlapping peptide 20mers, demonstrated that the antimicrobial activity is mediated by the unstructured N-terminal part of the protein. Synthetic peptides of the N-terminus of PrP killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, and the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen after treatment with the "classical" human antimicrobial peptide LL-37. In contrast to LL-37, however, no marked helix induction was detected for the PrP-derived peptides in presence of negatively charged (bacteria-mimicking) liposomes. PrP furthermore showed an inducible expression during wounding of human skin ex vivo and in vivo, as well as stimulation of keratinocytes with TGF-alpha in vitro.

Conclusions: The demonstration of an antimicrobial activity of PrP, localisation of its activity to the N-terminal and heparin-binding region, combined with results showing an increased expression of PrP during wounding, indicate that PrPs could have a previously undisclosed role in host defense.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents / pharmacology*
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / pharmacology
  • Bacillus subtilis / metabolism
  • Candida / metabolism
  • Candida albicans / metabolism
  • Escherichia coli / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Keratinocytes / metabolism
  • Microbial Sensitivity Tests*
  • Prions / chemistry
  • Prions / metabolism*
  • Protein Structure, Tertiary
  • Pseudomonas aeruginosa / metabolism
  • Staphylococcus aureus / metabolism
  • Transforming Growth Factor alpha / metabolism

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Prions
  • Transforming Growth Factor alpha
  • CAP18 lipopolysaccharide-binding protein