title: "Ciliophagy": The consumption of cilia components by autophagy.
abstract: Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) associated with respiratory epithelial cell cilia shortening and impaired mucociliary clearance (MCC). The underlying cellular and molecular mechanisms for CS-associated cilia shortening have remained incompletely understood. We have previously demonstrated increased autophagy in the lungs of COPD patients; however, whether or not this process is selective for specific autophagic targets in the lung was not elucidated. Based on observations that increased morphological and biochemical indicators of autophagy correlate with cilia shortening in our models, we posited that autophagy might regulate cilia length in response to CS in the lung. We demonstrate that CS-induced cilia shortening occurs through an autophagy-dependent mechanism mediated by the deacetylase HDAC6 (histone deacetylase 6). Autophagy-impaired (Becn1(+/-), map1lc3b(-/-), or Hdac6(-/Y)) mice resist CS-induced cilia shortening. Furthermore, cilia components are identified as autophagic substrates during CS exposure. Assessment of airway cilia function using a 3D MCC assay demonstrates that Becn1(+/-), map1lc3b(-/-), and Hdac6(-/Y) mice or mice injected with the HDAC6 inhibitor tubastatin A are protected from CS-associated mucociliary dysfunction. We concluded that an autophagy-dependent pathway regulates cilia length during CS exposure, which identifies new pathways and targets in COPD.
authors.affiliation: Division of Pulmonary and Critical Care Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA; Pulmonary and Critical Care Medicine; Weill Cornell Medical College; New York, NY USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cloonan
authors.affiliation: Division of Pulmonary and Critical Care Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA.
authors.forename: Hilaire C
authors.initials: HC
authors.lastname: Lam
authors.affiliation: Division of Pulmonary and Critical Care Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: Division of Pulmonary and Critical Care Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA; Pulmonary and Critical Care Medicine; Weill Cornell Medical College; New York, NY USA.
authors.forename: Augustine M
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D002923:Cilia / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*
chemical_list: D008869:Microtubule-Associated Proteins
keywords: COPD; HDAC6; autophagy; cilia; lung