Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction

Lam HC, Cloonan SM, Bhashyam AR, Haspel JA, Singh A, Sathirapongsasuti JF, Cervo M, Yao H, Chung AL, Mizumura K, An CH, Shan B, Franks JM, Haley KJ, Owen CA, Tesfaigzi Y, Washko GR, Quackenbush J, Silverman EK, Rahman I, Kim HP, Mahmood A, Biswal SS, Ryter SW, Choi AM

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)5212-30
JournalJournal of Clinical Investigation
Volume123
Issue number12
DOIs
Publication statusPublished - 2 Dec 2013

Keywords

  • Animals
  • Apoptosis Regulatory Proteins
  • Autophagy
  • Cells, Cultured
  • Cilia
  • Cytosol
  • Epithelial Cells
  • Female
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Scanning
  • Microtubule-Associated Proteins
  • Mucus
  • NF-E2-Related Factor 2
  • Phenotype
  • Phenylbutyrates
  • Proteasome Endopeptidase Complex
  • Protein Processing, Post-Translational
  • Pulmonary Disease, Chronic Obstructive
  • Sirtuin 1
  • Tobacco Products
  • Tobacco Smoke Pollution
  • Trachea
  • Ubiquitination

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