Human proteinase 3 resistance to inhibition extends to alpha-2 macroglobulin.

Human proteinase 3 resistance to inhibition extends to alpha-2 macroglobulin.:

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Human proteinase 3 resistance to inhibition extends to alpha-2 macroglobulin.

FEBS J. 2020 Jan 29;:

Authors: N'Guessan K, Grzywa R, Seren S, Gabant G, Juliano MA, Moniatte M, van Dorsselaer A, Bieth J, Kellenberger C, Gauthier F, Wysocka M, Lesner A, Sienczyk M, Cadene M, Korkmaz B

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 α2-macroglobulin (α2-M), serpins (α1-proteinase inhibitor (α1-PI)), monocyte neutrophil elastase inhibitor (MNEI), α1-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 α1-PI and MNEI but not by SLPI. α2-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 α2-M was more rapidly processed by hNE than hPR3 or hCatG. This was confirmed by the observation that the association between α2-M and hPR3 is governed by a kass in the ≤105 M- 1.s-1 range. Since α2-M-trapped proteinases retain peptidase activity, we first predicted the putative cleavage sites within the α2-M bait region (residues 690-728) 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 α2-M (39pep-α2-M). Since the 39pep-α2-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 α2-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.

PMID: 31995266 [PubMed - as supplied by publisher]