Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis.
Journal of Biological Chemistry. 2018-08-01; 293(32): 12415-12428
DOI: 10.1074/jbc.ra118.001922
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1. J Biol Chem. 2018 Aug 10;293(32):12415-12428. doi: 10.1074/jbc.RA118.001922. Epub
2018 Jun 20.
Consequences of cathepsin C inactivation for membrane exposure of proteinase 3,
the target antigen in autoimmune vasculitis.
Seren S(1), Rashed Abouzaid M(2), Eulenberg-Gustavus C(3), Hirschfeld J(4), Nasr
Soliman H(5), Jerke U(3), N’Guessan K(1), Dallet-Choisy S(1), Lesner A(6),
Lauritzen C(7), Schacher B(8), Eickholz P(8), Nagy N(9), Szell M(9), Croix C(10),
Viaud-Massuard MC(10), Al Farraj Aldosari A(11), Ragunatha S(12), Ibrahim Mostafa
M(2), Giampieri F(13), Battino M(13), Cornillier H(14), Lorette G(15), Stephan
JL(16), Goizet C(17), Pedersen J(7), Gauthier F(1), Jenne DE(18)(19),
Marchand-Adam S(1), Chapple IL(4), Kettritz R(3)(20), Korkmaz B(21).
Author information:
(1)From the INSERM U-1100, “Centre d’Etude des Pathologies Respiratoires” and
Université de Tours, 37000 Tours, France.
(2)the Departments of Oro-Dental Genetics and.
(3)the Experimental and Clinical Research Center, Charité und
Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC),
13125 Berlin, Germany.
(4)the Institute of Clinical Sciences, College of Medical and Dental Sciences,
Periodontal Research Group, University of Birmingham and Birmingham Community
Health Trust, Edgbaston, Birmingham B5 7EG, United Kingdom.
(5)Medical Molecular Genetics, National Research Centre, Cairo 12622, Egypt.
(6)the Faculty of Chemistry, University of Gdansk, 80-309 Gdansk, Poland.
(7)Unizyme Laboratories A/S, 2970 Hørsholm, Denmark.
(8)the Department of Periodontology, Johann Wolfgang Goethe-University Frankfurt,
60323 Frankfurt, Germany.
(9)the Department of Medical Genetics, University of Szeged, Szeged 6720,
Hungary.
(10)UMR-CNRS 7292 “Génétique, Immunothérapie, Chimie et Cancer” and Université
François Rabelais, 37000 Tours, France.
(11)the Department of Prosthetic Dental Science, College of Dentistry, King Saud
University, Riyadh 12372, Kingdom of Saudi Arabia.
(12)the Department of Dermatology, Venereology, and Leprosy, ESIC Medical College
and PGIMSR Rajajinagar, Bengaluru, Karnataka 560010, India.
(13)the Department of Clinical Sciences, Università Politecnica delle Marche,
60121 Ancona, Italy.
(14)Service de Dermatologie, Centre Hospitalier Universitaire de Tours,
Université de Tours, 37000 Tours, France.
(15)UMR-INRA1282 “Laboratoire de Virologie et Immunologie Moléculaires,”
Université de Tours, 37000 Tours, France.
(16)the Service d’Hématologie Immunologie et Rhumatologie Pédiatrique, Centre
Hospitalier Universitaire de Saint-Etienne, 42270 Saint-Priest-en-Jarez, France.
(17)INSERM U-1211, Rare Diseases, Genetic and Metabolism, MRGM Laboratory,
Pellegrin Hospital and University, 33000 Bordeaux, France.
(18)the Comprehensive Pneumology Center, Institute of Lung Biology and Disease,
German Center for Lung Research (DZL), 81377 Munich, Germany.
(19)the Max Planck Institute of Neurobiology, 82152 Planegg-Martinsried, Germany,
and.
(20)the Division of Nephrology and Intensive Care Medicine, Medical Department,
Charité-Universitätsmedizin, 10117 Berlin, Germany.
(21)From the INSERM U-1100, “Centre d’Etude des Pathologies Respiratoires” and
Université de Tours, 37000 Tours, France, .
Membrane-bound proteinase 3 (PR3m) is the main target antigen of anti-neutrophil
cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic
small-vessel vasculitis. Binding of ANCA to PR3m 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 PR3m and therefore has implications
as a novel therapeutic approach in granulomatosis with polyangiitis. We first
studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre 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
PR3m 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 PR3m on PLS neutrophils, whereas the total amount
of PR3m 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
PR3m, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil
differentiation was not compromised.
© 2018 Seren et al.
DOI: 10.1074/jbc.RA118.001922
PMCID: PMC6093229
PMID: 29925593 [Indexed for MEDLINE]