RRC ID 28084
Author 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.
Title Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction.
Journal J Clin Invest
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.
Volume 123(12)
Pages 5212-30
Published 2013-12-1
DOI 10.1172/JCI69636
PII 69636
PMID 24200693
PMC PMC3859407
MeSH Animals Apoptosis Regulatory Proteins / deficiency Autophagy / physiology* Beclin-1 Cells, Cultured Cilia / physiology* Cilia / ultrastructure Cytosol / enzymology Epithelial Cells / ultrastructure Female Histone Deacetylase 6 Histone Deacetylase Inhibitors / pharmacology Histone Deacetylases / physiology* Humans Male Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Electron, Scanning Microtubule-Associated Proteins / deficiency Mucus NF-E2-Related Factor 2 / deficiency NF-E2-Related Factor 2 / physiology Phenotype Phenylbutyrates / pharmacology Proteasome Endopeptidase Complex / metabolism Protein Processing, Post-Translational Pulmonary Disease, Chronic Obstructive / enzymology* Pulmonary Disease, Chronic Obstructive / etiology Pulmonary Disease, Chronic Obstructive / pathology Sirtuin 1 / deficiency Sirtuin 1 / physiology Tobacco Products Tobacco Smoke Pollution / adverse effects* Trachea / cytology Ubiquitination
IF 11.864
Times Cited 159
Mice RBRC00806