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Seren, S.* ; Rashed Abouzaid, M.* ; Eulenberg-Gustavus, C.* ; Hirschfeld, J.* ; Soliman, H.* ; Jerke, U.* ; N'Guessan, K.* ; Dallet-Choisy, S.* ; Lesner, A.* ; Lauritzen, C.* ; Schacher, B.* ; Eickholz, P.* ; Nagy, N.* ; Széll, M.* ; Croix, C.* ; Viaud-Massuard, M.C.* ; Al Farraj Aldosari, A.* ; Ragunatha, S.* ; Ibrahim Mostafa, M.* ; Giampieri, F.* ; Battino, M.* ; Cornillier, H.* ; Lorette, G.* ; Stephan, J.L.* ; Goizet, C.* ; Pedersen, J.* ; Gauthier, F.* ; Jenne, D. ; Marchand-Adam, S.* ; Chapple, I.L.* ; Kettritz, R.* ; Korkmaz, B.*

Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis.

J. Biol. Chem. 293, 12415-12428 (2018)
Verlagsversion Postprint Forschungsdaten DOI PMC
Open Access Green
Membrane-bound proteinase 3 (PR3(m)) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3(m) triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3(m) and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefevre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3(m) expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3(m) on PLS neutrophils, whereas the total amount of PR3(m) on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34(+) hematopoietic stem cell model. Human CD34(+) hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3(m), cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Protease ; Protease Inhibitor ; Neutrophil ; Aminopeptidase ; Antigen ; Autoimmune Disease ; Genetic Disease ; Proteinase 3 ; Cathepsin C ; Granulomatosis With Polyangiitis ; Papillon-lefevre Syndrome; Papillon-lefevre-syndrome; Anca-associated Vasculitides; Neutrophil Serine Proteases; Wegeners Autoantigen; Molecular Analysis; Human-diseases; Mutations; Elastase; Cells; Binding
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 293, Heft: 32, Seiten: 12415-12428 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa
Begutachtungsstatus