Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment

Bullón, P. et al. (2018) Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment. Journal of Allergy and Clinical Immunology, 142(4), 1131-1143.e7. (doi: 10.1016/j.jaci.2018.01.018) (PMID:29410039)

Abstract

Background Cathepsin C (CatC) is a lysosomal enzyme involved in activation of serine proteases from immune and inflammatory cells. Several loss-of-function mutations in the CatC gene have been shown to be the genetic mark of Papillon-Lefèvre syndrome (PLS), a rare autosomal recessive disease characterized by severe early-onset periodontitis, palmoplantar hyperkeratosis, and increased susceptibility to infections. Deficiencies or dysfunction in other cathepsin family proteins, such as cathepsin B or D, have been associated with autophagic and lysosomal disorders. Objectives Here we characterized the basis for autophagic dysfunction in patients with PLS by analyzing skin fibroblasts derived from patients with several mutations in the CatC gene and reduced enzymatic activity. Methods Skin fibroblasts were isolated from patients with PLS assessed by using genetic analysis. Authophagic flux dysfunction was evaluated by examining accumulation of p62/SQSTM1 and a bafilomycin assay. Ultrastructural analysis further confirmed abnormal accumulation of autophagic vesicles in mutant cells. A recombinant CatC protein was produced by a baculovirus system in insect cell cultures. Results Mutant fibroblasts from patients with PLS showed alterations in oxidative/antioxidative status, reduced oxygen consumption, and a marked autophagic dysfunction associated with autophagosome accumulation. These alterations were accompanied by lysosomal permeabilization, cathepsin B release, and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Treatment of mutant fibroblasts with recombinant CatC improved cell growth and autophagic flux and partially restored lysosomal permeabilization. Conclusions Our data provide a novel molecular mechanism underlying PLS. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for PLS.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Castejon Vega, Dr Beatriz
• Authors: Bullón, P., Castejón-Vega, B., Román-Malo, L., Jimenez-Guerrero, M. P., Cotán, D., Forbes-Hernandez, T. Y., Varela-López, A., Pérez-Pulido, A. J., Giampieri, F., Quiles, J. L., Battino, M., Sánchez-Alcázar, J. A., and Cordero, M. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Journal of Allergy and Clinical Immunology
• Publisher: Elsevier
• ISSN: 0091-6749
• ISSN (Online): 1097-6825
• Published Online: 02 February 2018