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

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

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 10

Schematic of ciliophagy.

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Schematic of ciliophagy. CS induces oxidative stress, which leads to cil...
CS induces oxidative stress, which leads to ciliary protein damage, misfolding, ubiquitination, and the formation of intracellular protein aggregates. HDAC6 recognizes ubiquitinated protein aggregates and delivers them to the autophagosome, a process dependent on the autophagy proteins LC3B and beclin 1. Ciliary proteins are delivered to the lysosome for degradation or recycling. In cases of chronic oxidative stress, ciliary proteins are degraded, resulting in a shortening of airway cilia that contributes to impaired MCC. Genetic deletion of LC3B (Map1lc3b), beclin 1 (Becn1), or HDAC6 (Hdac6), or inhibition of HDAC6 (tubastatin A) or protein misfolding (4-PBA) alleviates CS-induced impairment of MCC. Severe oxidative stress eventually leads to programmed epithelial cell death, a process that may involve excessive autophagy.