title: p62 sequestosome 1/light chain 3b complex confers cytoprotection on lung epithelial cells after hyperoxia.
abstract: Lung epithelial cell death is a prominent feature of hyperoxic lung injury, and has been considered a very important underlying mechanism of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Here we report on a novel mechanism involved in epithelial cytoprotection and homeostasis after oxidative stress. p62 (sequestosome 1; SQSTM1) is a ubiquitously expressed cellular protein. It interacts with ubiquitinated proteins and autophagic marker light chain 3b (LC3b), thus mediating the degradation of selective targets. In this study, we explored the role of p62 in mitochondria-mediated cell death after hyperoxia. Lung alveolar epithelial cells demonstrate abundant p62 expression, and p62 concentrations are up-regulated by oxidative stress at both the protein and mRNA levels. The p62/LC3b complex interacts with Fas and truncated BID (tBID) physically. These interactions abruptly diminish after hyperoxia. The deletion of p62 robustly increases tBID and cleaved caspase-3, implying an antiapoptotic effect. This antiapoptotic effect of p62 is further confirmed by measuring caspase activities, cleaved poly ADP ribose polymerase, and cell viability. The deletion of the p62 PBI domain or the ubiquitin-associated domain both lead to elevated tBID, cleaved caspase-3, and significantly more cell death after hyperoxia. Moreover, p62 traffics in an opposite direction with LC3b after hyperoxia, leading to the dissociation of the p62/Cav-1/LC3b/BID complex. Subsequently, the LC3b-mediated lysosomal degradation of tBID is eliminated. Taken together, our data suggest that the p62/LC3b complex regulates lung alveolar epithelial cell homeostasis and cytoprotection after hyperoxia.
authors: Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Xiaoliang
authors: X
authors: Liang
authors: Shu-Quan
authors: SQ
authors: Wei
authors: Seon-Jin
authors: SJ
authors: Lee
authors: James K
authors: JK
authors: Fung
authors: Meng
authors: M
authors: Zhang
authors: Akihiko
authors: A
authors: Tanaka
authors: Augustine M K
authors: AM
authors: Choi
authors: Yang
authors: Y
authors: Jin
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D018384:Oxidative Stress; D059748:Proteolysis; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D036002:ADP Ribose Transferases; C505409:Casp3 protein, mouse; D053148:Caspase 3