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  NSP4, an elastase-related protease in human neutrophils with arginine specificity

Perera, N. C., Schilling, O., Kittel, H., Back, W., Kremmer, E., & Jenne, D. E. (2012). NSP4, an elastase-related protease in human neutrophils with arginine specificity. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109(16), 6229-6234. doi:10.1073/pnas.1200470109.

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Perera, Natascha C.1, Autor           
Schilling, Oliver2, Autor
Kittel, Heike1, Autor           
Back, Walter2, Autor
Kremmer, Elisabeth2, Autor
Jenne, Dieter E.1, Autor           
Affiliations:
1Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society, ou_1113547              
2External Organizations, ou_persistent22              

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Schlagwörter: CATHEPSIN-G; PEPTIDE LIBRARIES; CLEAVAGE SITES; INFLAMMATION; PROTEINASE-3; IMMUNITY; RELEASE; MODELtissue distribution; serpins; cleavage site; proteomics; evolution;
 Zusammenfassung: Neutrophil serine proteases (NSPs) in cytoplasmic granules of neutrophils are regarded as important antimicrobial defense weapons after engulfment and exposure of pathogens to the content of primary granules. Despite intensive studies on neutrophils during the last three decades, only three active serine proteases, neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3) have been identified in these short-lived cells. Here, we report on the identification of a fourth serine protease (NSP4) with 39% identity to NE and PR3, but arginine specificity, yet sharing features like propeptide processing by dipeptidyl peptidase I, storage, and release as an active enzyme with the three active proteases. We established monoclonal antibodies against NSP4, excluded cross-reactivity to human gran-zymes, NE, CG, PR3, and azurocidin, and screened for NSP4 protein expression in various human tissues and blood leukocyte populations. Only granulocyte precursors and neutrophil populations from peripheral blood were positive. The content of NSP4 in neutrophil lysates, however, was about 20-fold lower compared with CG. Upon neutrophil activation, NSP4 was released into the supernatant. Profiling its specificity with peptide libraries from Escherichia coli revealed a preference for arginine in P1; it cleaved Tyr-Arg-Phe-Arg-AMC and Ala-Pro-Nva-thiobenzyl esters. NSP4 was inhibited by alpha(1)-proteinase inhibitor (alpha 1-antitrypsin), C1 inhibitor, and most efficiently by antithrombin-heparin, but not by elafin, secretory leukocyte protease inhibitor, alpha 1-antichymotrypsin, and monocyte-neutrophil elastase inhibitor. Functional specialization and preferred natural substrates of NSP4 remain to be determined to understand the biological interplay of all four NSPs during neutrophil responses.

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Sprache(n): eng - English
 Datum: 2012-04-17
 Publikationsstatus: Erschienen
 Seiten: 6
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: ISI: 000303246100066
DOI: 10.1073/pnas.1200470109
 Art des Abschluß: -

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Titel: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA : NATL ACAD SCIENCES
Seiten: - Band / Heft: 109 (16) Artikelnummer: - Start- / Endseite: 6229 - 6234 Identifikator: ISSN: 0027-8424