title: Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction.
abstract: Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1+/- or Map1lc3B-/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6-/Y) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1-/-, Map1lc3B-/-, and Hdac6-/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.
authors.forename: Hilaire C
authors.initials: HC
authors.lastname: Lam
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cloonan
authors.forename: Abhiram R
authors.initials: AR
authors.lastname: Bhashyam
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Haspel
authors.forename: Anju
authors.initials: A
authors.lastname: Singh
authors.forename: J Fah
authors.initials: JF
authors.lastname: Sathirapongsasuti
authors.forename: Morgan
authors.initials: M
authors.lastname: Cervo
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Anna L
authors.initials: AL
authors.lastname: Chung
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.forename: Chang Hyeok
authors.initials: CH
authors.lastname: An
authors.forename: Bin
authors.initials: B
authors.lastname: Shan
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Franks
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Mahmood
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Biswal
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; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002478:Cells, Cultured; D002923:Cilia / Q000502:physiology* / Q000648:ultrastructure; D003600:Cytosol / Q000201:enzymology; D004847:Epithelial Cells / Q000648:ultrastructure; D005260:Female; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D008869:Microtubule-Associated Proteins / Q000172:deficiency; D009093:Mucus; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000502:physiology; D010641:Phenotype; D010654:Phenylbutyrates / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D056564:Sirtuin 1 / Q000172:deficiency / Q000502:physiology; D062789:Tobacco Products; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014132:Trachea / Q000166:cytology; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D056572:Histone Deacetylase Inhibitors; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010654:Phenylbutyrates; D014028:Tobacco Smoke Pollution; C075773:4-phenylbutyric acid; D046988:Proteasome Endopeptidase Complex; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases