@article {1433714,
	title = {Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction},
	journal = {J Clin Invest},
	volume = {123},
	number = {12},
	year = {2013},
	month = {2013 Dec},
	pages = {5212-30},
	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. },
	keywords = {Animals, Apoptosis Regulatory Proteins, Autophagy, Beclin-1, Cells, Cultured, Cilia, Cytosol, Epithelial Cells, Female, Histone Deacetylase 6, 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},
	issn = {1558-8238},
	doi = {10.1172/JCI69636},
	author = {Lam, Hilaire C and Cloonan, Suzanne M and Bhashyam, Abhiram R and Haspel, Jeffery A and Singh, Anju and Sathirapongsasuti, J Fah and Cervo, Morgan and Hongwei Yao and Chung, Anna L and Mizumura, Kenji and An, Chang Hyeok and Shan, Bin and Franks, Jonathan M and Haley, Kathleen J and Owen, Caroline A and Tesfaigzi, Yohannes and Washko, George R and Quackenbush, John and Silverman, Edwin K and Irfan Rahman and Kim, Hong Pyo and Mahmood, Ashfaq and Biswal, Shyam S and Ryter, Stefan W and Choi, Augustine M K}
}