Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

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.

The Role of Mitochondria and Oxidative/Antioxidative Imbalance in Pathobiology of Chronic Obstructive Pulmonary Disease

“…One of them, cathepsin E (CE), may directly influence mitochondrial function. Human lung sections from patients with COPD indicated increased expression of CE protein in the lung epithelial cells [176]. Unlike other members of cathepsin family, CE has not been reported to exhibit proteolytic activity.…”

“…Unlike other members of cathepsin family, CE has not been reported to exhibit proteolytic activity. CE overexpression seems to lead to pulmonary emphysema by increasing mitochondrial fission via dynamin-related protein 1 induction, Parkin, and ubiquitin-proteasome system, thereby influencing the mitochondrial fusion-fission balance, leading to increased caspase 3-mediated cell death (Figure 2) [176]. …”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…Abnormal expression and/or activity of CTSs have been associated with a variety of human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and many others ( Table 1). [37,45] [ 46,47] [48] Figure 1. Cellular localization of cathepsins (CTSs).…”

Bcl-2 Proteins Regulate Mitophagy in Lipopolysaccharide-Induced Acute Lung Injury via PINK1/Parkin Signaling Pathway

“…Oxidative Medicine and Cellular Longevity downregulated following Parkin KO [44]. Therefore, it can be speculated that Parkin mediates bidirectional regulation of Drp1.…”