@misc{10481/64979,
year = {2018},
url = {http://hdl.handle.net/10481/64979},
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-Lef evre 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. (J Allergy Clin Immunol 2018;142:1131-43.)},
organization = {Proyecto de Investigacion de Excelencia de la Junta de Andalucia 	
CTS113},
organization = {Instituto de Salud Carlos III

PI16/00786},
organization = {Fondo Europeo de Desarrollo Regional (FEDER-Union Europea)},
publisher = {MOSBY-ELSEVIER},
keywords = {Papillon-Lefevre syndrome},
keywords = {Cathepsin C},
keywords = {Autophagy},
keywords = {Lysosomal permeabilization},
title = {Autophagic dysfunction in patients with papillon-lefevre syndrome is restored by recombinant cathepsin C treatment},
doi = {10.1016/j.jaci.2018.01.018},
author = {Bullón, Pedro and Varela López, Alfonso and Quiles Morales, José Luis and Cordero, Mario},
}