Autophagic dysfunction in Papillon Lefèvre syndrome is restored by recombinant Cathepsin C treatment

Publication date: Available online 2 February 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Pedro Bullón, Beatriz Castejón-Vega, Lourdes Román-Malo, María Paz Jimenez-Guerrero, David Cotán, Tamara Y. Forbes-Hernandez, Alfonso Varela-López, Antonio Pérez-Pulido, Francesca Giampieri, José L. Quiles, Maurizio Battino, José A. Sánchez-Alcázar, Mario D. Cordero
BackgroundCathepsin C (CatC) is a lysosomal enzyme involved in the activation of serine proteases from immune and inflammatory cells. Several mutations with loss of function in the Cathepsin C (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 B or D have been associated with autophagic and lysosomal disorders.ObjectivesHere, we characterized the basis for autophagic dysfunction in PLS by analyzing skin fibroblasts derived from patients with several mutations in the CatC gene and reduced enzymatic activity.MethodsSkin fibroblasts were isolated from PLS patients assessed by genetic analysis. Authophagy flux dysfunction was evaluated by examining the accumulation of p62/SQSTM1 and a bafilomycin assay. Ultrastructural analysis further confirmed an abnormal accumulation of autophagic vesicles in mutant cells. A recombinant recombinant CatC (rCatC) protein was produced by a baculovirus system in insect cell cultures.ResultsPLS mutant fibroblasts showed alterations in the oxidative/antioxidative status, reduced oxygen consumption and a marked autophagic dysfunction associated with autophagosome accumulation. These alterations were accompanied by lysosomal permeabilization, CatB release and NLRP3-inflammasome activation. Treatment of mutant fibroblasts with rCatC improved cell growth, autophagic flux and partially restored lysosomal permeabilization.ConclusionsOur data provide a novel molecular mechanism underlying PLS. Impaired autophagy caused by insufficient lysosomal function may represent a new therapeutic target for PLS.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2s25odj