title: Proteolytic activation transforms heparin cofactor II into a host defense molecule.
abstract: The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.
authors: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden.
authors: Martina
authors: M
authors: Kalle
authors: Praveen
authors: P
authors: Papareddy
authors: Gopinath
authors: G
authors: Kasetty
authors: Douglas M
authors: DM
authors: Tollefsen
authors: Martin
authors: M
authors: Malmsten
authors: Matthias
authors: M
authors: Mörgelin
authors: Artur
authors: A
authors: Schmidtchen
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D015844:Heparin Cofactor II / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059748:Proteolysis
chemical_list: D023181:Antimicrobial Cationic Peptides; D015844:Heparin Cofactor II
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