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


RESULTS
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.
Pasupuleti
Mukesh
M
Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden. mukesh.pasupuleti@med.lu.se
Roupe
Markus
M
Rydengård
Victoria
V
Surewicz
Krystyna
K
Surewicz
Witold K
WK
Chalupka
Anna
A
Malmsten
Martin
M
Sörensen
Ole E
OE
Schmidtchen
Artur
A
D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000378:metabolism; D002175:Candida / Q000378:metabolism; D002176:Candida albicans / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015603:Keratinocytes / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D054804:Cathelicidins
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D011328:Prions; D016211:Transforming Growth Factor alpha; D054804:Cathelicidins