title: 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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut.
authors.forename: Xuchen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Peiying
authors.initials: P
authors.lastname: Shan
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut.
authors.forename: Robert
authors.initials: R
authors.lastname: Homer
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, Center for Immunobiology, Indiana University, Indianapolis, Indiana.
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Praveen
authors.initials: P
authors.lastname: Mannam
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut. Electronic address: patty.lee@yale.edu.
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D018893:Bronchoalveolar Lavage; D020059:Cathepsin E / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063154:Mitochondrial Dynamics; D009842:Oligopeptides / Q000494:pharmacology; D011656:Pulmonary Emphysema / Q000378:metabolism* / Q000503:physiopathology; D052999:Quinazolinones / Q000494:pharmacology; D012906:Smoke / Q000009:adverse effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D009842:Oligopeptides; D052999:Quinazolinones; D012906:Smoke; D014028:Tobacco Smoke Pollution; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D020059:Cathepsin E; C533926:Ctse protein, mouse; C533925:CTSE protein, human