Journal
FEBS JOURNAL
Volume 287, Issue 18, Pages 4068-4081Publisher
WILEY
DOI: 10.1111/febs.15229
Keywords
proteinase 3; proteolysis; serine proteinase; alpha 2-macroglobulin
Categories
Funding
- Region Centre-Val de Loire
- European FEDER Program [2017-EX002979]
- Wrocaw University of Science and Technology [049U/0096/19]
Ask authors/readers for more resources
Polymorphonuclear neutrophils contain at least four serine endopeptidases, namely neutrophil 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 alpha 2-macroglobulin (alpha 2-M), serpins [alpha 1-proteinase inhibitor (alpha 1-PI)], monocyte neutrophil elastase inhibitor (MNEI), alpha 1-antichymotrypsin, and locally produced chelonianins (elafin, SLPI) control excessive proteolytic activity of neutrophilic serine proteinases. In contrast to human NE (hNE), hPR3 is weakly inhibited by alpha 1-PI and MNEI but not by SLPI. alpha 2-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 alpha 2-M was more rapidly processed by hNE than hPR3 or hCatG. This was confirmed by the observation that the association between alpha 2-M and hPR3 is governed by a k(ass) in the <= 10(5) m(-1)center dot s(-1) range. Since alpha 2-M-trapped proteinases retain peptidase activity, we first predicted the putative cleavage sites within the alpha 2-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 alpha 2-M (39pep-alpha 2-M). Since the 39pep-alpha 2-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 alpha 2-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 autoantigen in granulomatosis with polyangiitis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available