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dc.contributor.authorMercado, Nicolas
dc.contributor.authorColley, Thomas
dc.contributor.authorBaker, Jonathan R.
dc.contributor.authorVuppussetty, Chaitanya
dc.contributor.authorKono, Yuta
dc.contributor.authorClarke, Colin
dc.contributor.authorTooze, Sharon A
dc.contributor.authorJohansen, Terje
dc.contributor.authorBarnes, Peter J.
dc.date.accessioned2021-02-11T12:41:01Z
dc.date.available2021-02-11T12:41:01Z
dc.date.issued2019-09-26
dc.description.abstractBicaudal D1 (BICD1), an adaptor for the dynein‐dynactin motor complex, has been identified as a susceptibility gene in chronic obstructive pulmonary disease (COPD). Autophagy, an essential cellular homeostasis process, is defective in COPD, in which oxidative stress‐induced misfolded proteins accumulate into toxic aggregates dependent on the accumulation of the autophagic cargo receptor p62. Defective autophagy can be caused by mutations in the dynein and dynactin motor complex suggesting a possible link between BICD1 and defective autophagy in COPD. BICD1 levels were measured in peripheral lung tissue from COPD patients together with markers of autophagy and found to be increased in COPD together with autophagosomes, p62 and p62 oligomers. In vitro exposure of bronchial epithelial cells to cigarette smoke extracts (CSEs) revealed that high concentrations of CSE induced defective autophagosome maturation with accumulation of BICD1, p62 and ubiquitin‐associated p62 oligomers. This was confirmed in vivo using CS‐exposed mice. Furthermore, we identified that formation of CS‐induced p62 oligomers required an interaction with Keap1. Overexpression and ablation of BICD1 confirmed that increased BICD1 negatively regulates autophagosome maturation inducing accumulation of p62 and p62 oligomers and that it can be reversed by cardiac glycosides. We conclude that defective autophagosome maturation in COPD is caused by oxidative stress‐mediated BICD1 accumulation.en_US
dc.identifier.citationMercado, Colley, Baker, Vuppussetty, Kono, Clarke, Tooze SA, Johansen T, Barnes. Bicaudal D1 impairs autophagosome maturation in chronic obstructive pulmonary disease. FASEB BioAdvances. 2019;1:688-705en_US
dc.identifier.cristinIDFRIDAID 1888380
dc.identifier.doi10.1096/fba.2018-00055
dc.identifier.issn2573-9832
dc.identifier.urihttps://hdl.handle.net/10037/20553
dc.language.isoengen_US
dc.publisherWileyen_US
dc.relation.journalFASEB BioAdvances
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2019 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.titleBicaudal D1 impairs autophagosome maturation in chronic obstructive pulmonary diseaseen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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