Cathepsin E promotes pulmonary emphysema via mitochondrial fission

Xuchen Zhang, Peiying Shan, Robert Homer, Yi Zhang, Irina Petrache, Praveen Mannam, Patty J. Lee

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.

Original languageEnglish
Pages (from-to)2730-2741
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number10
DOIs
StatePublished - 2014

Fingerprint

Cathepsin E
Mitochondrial Dynamics
Pulmonary Emphysema
Emphysema
Lung
Dynamins
Cathepsins
Apoptosis
Chronic Obstructive Pulmonary Disease
Caspase 1
Proteins
Ubiquitin-Protein Ligases
Mitochondrial Proteins
Elasticity
Antigen Presentation
Caspases
Smoke
Tobacco Products
Lung Diseases
Cysteine

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Cathepsin E promotes pulmonary emphysema via mitochondrial fission. / Zhang, Xuchen; Shan, Peiying; Homer, Robert; Zhang, Yi; Petrache, Irina; Mannam, Praveen; Lee, Patty J.

In: American Journal of Pathology, Vol. 184, No. 10, 2014, p. 2730-2741.

Research output: Contribution to journalArticle

Zhang, X, Shan, P, Homer, R, Zhang, Y, Petrache, I, Mannam, P & Lee, PJ 2014, 'Cathepsin E promotes pulmonary emphysema via mitochondrial fission', American Journal of Pathology, vol. 184, no. 10, pp. 2730-2741. https://doi.org/10.1016/j.ajpath.2014.06.017
Zhang, Xuchen ; Shan, Peiying ; Homer, Robert ; Zhang, Yi ; Petrache, Irina ; Mannam, Praveen ; Lee, Patty J. / Cathepsin E promotes pulmonary emphysema via mitochondrial fission. In: American Journal of Pathology. 2014 ; Vol. 184, No. 10. pp. 2730-2741.
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