title: Deadly triplex: smoke, autophagy and apoptosis.
abstract: Autophagy, a cellular program for organelle and protein turnover, represents primarily a cell survival mechanism. However, the role of autophagy in the regulation of apoptosis remains unclear. We have observed increases in morphological and biochemical indicators of autophagy in human lung from patients with chronic obstructive pulmonary disease (COPD). Furthermore, we observed induction of autophagic markers in mouse lung subjected to chronic cigarette smoke exposure. Recently, we investigated the role of the autophagic protein microtubule-associated protein 1 light chain 3B (LC3B) as a regulator of lung cell death. We found that LC3B knockout (LC3B(-/-)) mice subjected to chronic cigarette smoke exposure have reduced lung apoptosis, and resist airspace enlargement, relative to wild-type mice. We therefore examined the mechanisms by which LC3B can regulate apoptosis in epithelial cells. We found that LC3B forms a complex with the death receptor Fas in lipid rafts of epithelial cells, which requires the caveolae-resident protein caveolin-1. Genetic interference of caveolin-1 in epithelial cells augments cigarette smoke-induced apoptosis. Caveolin-1 knockout mice exhibit increased autophagic markers, apoptosis, and airspace enlargement in the lung in response to chronic cigarette smoke. These studies demonstrate that LC3B can promote tissue injury during chronic cigarette smoke exposure, and suggest a mechanism by which LC3B, through interactions with caveolin-1 and Fas, can regulate apoptosis. Targeting the autophagic pathway may represent an experimental therapeutic strategy when designing new approaches to COPD treatment.
authors.affiliation: Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. sryter@partners.org
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Hilaire C
authors.initials: HC
authors.lastname: Lam
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D051242:Caveolin 1 / Q000378:metabolism; D016923:Cell Death; D008168:Lung / Q000473:pathology; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051242:Caveolin 1; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D019014:fas Receptor