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Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction
Hilaire C. Lam, … , Stefan W. Ryter, Augustine M.K. Choi
Hilaire C. Lam, … , Stefan W. Ryter, Augustine M.K. Choi
Published November 8, 2013
Citation Information: J Clin Invest. 2013;123(12):5212-5230. https://doi.org/10.1172/JCI69636.
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Research Article Pulmonology Article has an altmetric score of 13

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

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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

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 Rahman, Hong Pyo Kim, Ashfaq Mahmood, Shyam S. Biswal, Stefan W. Ryter, Augustine M.K. Choi

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Figure 3

Autophagy impairment prevents cilia shortening in response to CS.

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Autophagy impairment prevents cilia shortening in response to CS.
(A) Au...
(A) Autophagosomes per area were quantified from TEM images (10–15 images/mouse) of ciliated airway epithelial cells in Becn1+/+ and Becn1+/– mice exposed to RA or CS for 6 months (n = 2–4 /group). (B) Autophagic flux was assessed by LC3B turnover in Becn1+/+ and Becn1+/– mice exposed to CS or RA for 6 months (n = 3–4 mice/group). (C) Representative SEM in Becn1+/+ and Becn1+/– MTECs 24 hours after treatment with CS (50 mg/m3). Red arrows indicate intact cilia; red arrowheads indicate shortened cilia. Scale bar: 500 nm. (D) Change in cilia length and (E) cells with cilia lengths of 0.6 AU or more in Becn1+/+ and Becn1+/– MTECs 24 hours after treatment with CS (50 mg/m3). (F) Change in cilia length and (G) cells with cilia lengths of 0.6 AU or more in Map1lc3b+/+ and Map1lc3b–/– MTECs 24 hours after treatment with CS (50 mg/m3). MTEC cilia lengths were calculated from 10 SEM images per experiment (n = 3). The number of MTECs with cilia lengths of 0.6 AU or more were calculated from 5 SEM images per sample (n = 4 cultures/group) normalized to controls. (H and I) Change in cilia length in (H) Becn1+/+ and Becn1+/– mice or (I) in Map1lc3b+/+ and Map1lc3b–/– mice exposed to CS for 2 months (n = 4 mice/group; 10 H&E-stained images/mouse). The average cilia length per image was calculated by measuring >3 cilia for every ciliated cell and normalizing to controls. All data are the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 by one- or two-way ANOVA and Bonferroni’s post tests.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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