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NSP4, a novel elastase-related protease with unique specificity is produced by human neutrophils

Perera, Natascha C., Kittel, Heike, Walter, Back, Kremmer, Elisabeth and Jenne, Dieter E. (2012) NSP4, a novel elastase-related protease with unique specificity is produced by human neutrophils. Proceedings of the National Academy of Sciences of the United States of America, 109 (16). pp. 6229-6234. ISSN 0027-8424


Neutrophil serine proteases (NSPs) in cytoplasmic granules of neutrophils are regarded as important antimicrobial defence weapons after endocytosis and exposure of pathogens to the content of primary granules. Despite intensive studies on NSPs during the last three decades, only three active serine proteases, neutrophil elastase (NE), cathepsin G (CG) and proteinase 3 (PR3) expressed and stored by these short-lived cells were encountered. Here we report on the discovery of a fourth serine protease (NSP4) with unique elastase activity. Although amino acid residues are only 40% identical with PR3 and NE, many features like propeptide processing by cathepsin C, storage and release as an active enzyme and cleavage of Ala-Pro-Nva-thiobenzylesters are shared with them.
We prepared and identified specific monoclonal antibodies to NSP4 in rats, excluded cross-reactivity to all five granzymes, NE, CG, PR3, azurocidin and stained different human tissues and blood leukocyte populations. To our surprise only granulocyte precursors and neutrophil populations from peripheral blood were positive. Upon neutrophil activation, NSP4 was released into the supernatant, but the content of NSP4 in neutrophil lysates was about 20 fold lower than that of CG using purified CG and recombinant NSP4 as protein standards in Western blotting. NSP4 was active towards some tripeptide-thiobenzylesters cleaving after aliphatic hydrophobic residues. It was moderately inhibited by the natural serine protease inhibitors a1PI and elafin indicating a distinct extended peptide specificity of this novel NSP. Functional specialization and preferred natural substrates of NSP4 remain to be determined in order to understand the biological interplay of all four NSPs during neutrophil responses.

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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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