PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Perera, N.C.* ; Schilling, O.* ; Kittel, H.* ; Back, W.* ; Kremmer, E. ; Jenne, D.

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

Proc. Natl. Acad. Sci. U.S.A. 109, 6229-6234 (2012)
Publ. Version/Full Text Volltext DOI PMC
Open Access Gold
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 granzymes, 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 α(1)-proteinase inhibitor (α(1)-antitrypsin), C1 inhibitor, and most efficiently by antithrombin-heparin, but not by elafin, secretory leukocyte protease inhibitor, α(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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
9.681
0.807
79
78
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords tissue distribution; serpins; cleavage site; proteomics; evolution; CATHEPSIN-G; PEPTIDE LIBRARIES; CLEAVAGE SITES; INFLAMMATION; PROTEINASE-3; IMMUNITY; RELEASE; MODEL
Language
Publication Year 2012
HGF-reported in Year 2012
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 109, Issue: 16, Pages: 6229-6234 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30202 - Environmental Health
Research field(s) Immune Response and Infection
Lung Research
PSP Element(s) G-501793-001
G-501600-005
PubMed ID 22474388
DOI 10.1073/pnas.1200470109
WOS ID 000303246100066
Scopus ID 84859950056
Erfassungsdatum 2012-06-13
[➜Report correction]