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

Hilaire C. Lam, Suzanne M. Cloonan, Abhiram R. Bhashyam, Jeffery A. Haspel, Anju Singh, J. Fah Sathirapongsasuti, Morgan Cervo, Hongwei Yao, Anna L. Chung, Kenji Mizumura, Chang Hyeok An, Bin Shan, Jonathan M. Franks, Kathleen J. Haley, Caroline A. Owen, Yohannes Tesfaigzi, George R. Washko, John Quackenbush, Edwin K. Silverman, Irfan RahmanHong Pyo Kim, Ashfaq Mahmood, Shyam S. Biswal, Stefan W. Ryter, Augustine M.K. Choi

Research output: Contribution to journalArticle

152 Scopus citations

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)5212-5230
Number of pages19
JournalJournal of Clinical Investigation
Volume123
Issue number12
DOIs
StatePublished - Dec 2 2013
Externally publishedYes

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    Lam, H. C., Cloonan, S. M., Bhashyam, A. R., Haspel, J. A., Singh, A., Sathirapongsasuti, J. F., Cervo, M., Yao, H., Chung, A. L., Mizumura, K., An, C. H., Shan, B., Franks, J. M., Haley, K. J., Owen, C. A., Tesfaigzi, Y., Washko, G. R., Quackenbush, J., Silverman, E. K., ... Choi, A. M. K. (2013). Histone deacetylase 6-mediated selective autophagy regulates copd-associated cilia dysfunction. Journal of Clinical Investigation, 123(12), 5212-5230. https://doi.org/10.1172/JCI69636