The abnormal accumulation of heparan sulfate in patients with mucopolysaccharidosis prevents the elastolytic activity of cathepsin V

Thibault Chazeirat, Sophie Denamur, Krzysztof K. Bojarski, Pierre Marie Andrault, Damien Sizaret, Fuming Zhang, Ahlame Saidi, Marine Tardieu, Robert J. Linhardt, François Labarthe, Dieter Brömme, Sergey A. Samsonov, Gilles Lalmanach, Fabien Lecaille

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Mucopolysaccharidosis (MPS) are rare inherited diseases characterized by accumulation of lysosomal glycosaminoglycans, including heparan sulfate (HS). Patients exhibit progressive multi-visceral dysfunction and shortened lifespan mainly due to a severe cardiac/respiratory decline. Cathepsin V (CatV) is a potent elastolytic protease implicated in extracellular matrix (ECM) remodeling. Whether CatV is inactivated by HS in lungs from MPS patients remained unknown. Herein, CatV colocalized with HS in MPS bronchial epithelial cells. HS level correlated positively with the severity of respiratory symptoms and negatively to the overall endopeptidase activity of cysteine cathepsins. HS bound tightly to CatV and impaired its activity. Withdrawal of HS by glycosidases preserved exogenous CatV activity, while addition of Surfen, a HS antagonist, restored elastolytic CatV-like activity in MPS samples. Our data suggest that the pathophysiological accumulation of HS may be deleterious for CatV-mediated ECM remodeling and for lung tissue homeostasis, thus contributing to respiratory disorders associated to MPS diseases.

Original languageEnglish
Article number117261
JournalCarbohydrate Polymers
Volume253
DOIs
StatePublished - 1 Feb 2021
Externally publishedYes

Keywords

  • Elastin
  • Glycosaminoglycan
  • Lung
  • MPS
  • Protease

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