title: Hyperoxia-induced LC3B interacts with the Fas apoptotic pathway in epithelial cell death.
abstract: Epithelial cell death plays a critical role in hyperoxia-induced lung injury. We investigated the involvement of the autophagic marker microtubule-associated protein-1 light chain-3B (LC3B) in epithelial cell apoptosis after hyperoxia. Prolonged hyperoxia (>95% O(2)), which causes characteristic lung injury in mice, activated morphological and biochemical markers of autophagy. Hyperoxia induced the time-dependent expression and conversion of LC3B-I to LC3B-II in mouse lung in vivo and in cultured epithelial cells (Beas-2B, human bronchial epithelial cells) in vitro. Hyperoxia increased autophagosome formation in Beas-2B cells, as evidenced by electron microscopy and increased GFP-LC3 puncta. The augmented LC3B level after hyperoxia was transcriptionally regulated and dependent in part on the c-Jun N-terminal kinase pathway. We hypothesized that LC3B plays a regulatory role in hyperoxia-induced epithelial apoptosis. LC3B siRNA promoted hyperoxia-induced cell death in epithelial cells, whereas overexpression of LC3B conferred cytoprotection after hyperoxia. The autophagic protein LC3B cross-regulated the Fas apoptotic pathway by physically interacting with the components of death-inducing signaling complex. This interaction was mediated by caveolin-1 tyrosine 14, which is a known target of phosphorylation induced by hyperoxia. Taken together, hyperoxia-induced LC3B activation regulates the Fas apoptotic pathway and thus confers cytoprotection in lung epithelial cells. The interaction of LC3B and Fas pathways requires cav-1.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D053181:Caspase 8; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D014443:Tyrosine / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D015415:Biomarkers; C495540:CAV1 protein, human; D051242:Caveolin 1; C491901:FAS protein, human; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D019014:fas Receptor; D014443:Tyrosine; D048031:JNK Mitogen-Activated Protein Kinases; D053181:Caspase 8
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