Human proteinase 3 resistance to inhibition extends to alpha‐2 macroglobulin

Koffi N'Guessan , Renata Grzywa , Seda Seren , Guillaume Gabant , Maria A. Juliano , Marc Moniatte , Alain van Dorsselaer , Joseph Bieth , Christine Kellenberger , Francis Gauthier , Magdalena Wysocka , Adam Lesner , Marcin Sieńczyk , Martine Cadene , Brice Korkmaz

Abstract

Neutrophils contain at least four serine endopeptidases namely elastase (NE), proteinase 3 (PR3), cathepsin G (CatG) and NSP4, which contribute to the regulation of infection and of inflammatory processes. In physiological conditions, endogenous inhibitors including alpha2-macroglobulin (alpha2-M), serpins (alpha1-proteinase inhibitor (alpha1-PI)), monocyte neutrophil elastase inhibitor (MNEI), alpha1-antichymotrypsin) and locally produced chelonianins (elafin, SLPI) control excessive proteolytic activity of neutrophilic serine proteinases. In contrast to human elastase (hNE), hPR3 is weakly inhibited by alpha1-PI and MNEI but not by SLPI. alpha2-M is a large spectrum inhibitor that traps a variety of proteinases in response to cleavage(s) in its bait region. We report here that alpha2-M was more rapidly processed by hNE than hPR3 or hCatG. This was confirmed by the observation that the association between alpha2-M and hPR3 is governed by a kass in the ≤105 M- 1.s-1 range. Since alpha2-M-trapped proteinases retain peptidase activity, we first predicted the putative cleavage sites within the alpha2-M bait region (residues690-728) using kinetic and molecular modeling approaches. We then identified by mass spectrum analysis the cleavage sites of hPR3 in a synthetic peptide spanning the 39-residue bait region of alpha2-M (39pep-alpha2-M). Since the 39pep-alpha2-M peptide and the corresponding bait area in the whole protein do not contain sequences with a high probability of specific cleavage by hPR3 and were indeed only slowly cleaved by hPR3, it can be concluded that alpha2-M is a poor inhibitor of hPR3. The resistance of hPR3 to inhibition by endogenous inhibitors explains at least in part its role in tissue injury during chronic inflammatory diseases and its well-recognized function of major target auto-antigen in granulomatosis with polyangiitis.
Publication typeIn press (online first, early view)
Author Koffi N'Guessan
Koffi N'Guessan,,
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, Renata Grzywa
Renata Grzywa,,
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, Seda Seren
Seda Seren,,
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, Guillaume Gabant
Guillaume Gabant,,
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, Maria A. Juliano
Maria A. Juliano,,
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, Marc Moniatte
Marc Moniatte,,
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, Alain van Dorsselaer
Alain van Dorsselaer,,
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, Joseph Bieth
Joseph Bieth,,
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, Christine Kellenberger
Christine Kellenberger,,
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, Francis Gauthier
Francis Gauthier,,
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et al.`
Journal seriesFEBS Journal, ISSN 1742-464X, e-ISSN 1742-4658, (N/A 100 pkt)
Issue year2020
Noonline first
Pages1-1
Publication size in sheets0.3
Keywords in Englishproteinase 3, proteolysis, serine proteinase, alpha2-macroglobulin
ASJC Classification1303 Biochemistry; 1307 Cell Biology; 1312 Molecular Biology
DOIDOI:10.1111/febs.15229
Languageen angielski
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 17-02-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.148; WoS Impact Factor: 2018 = 4.739 (2) - 2018=4.432 (5)
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