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

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Molecular Biology

Background:

• Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and impaired airway function due to cigarette smoke (CS).
• CS exposure disrupts epithelial cell function, leading to cilia shortening and compromised mucociliary clearance (MCC).
• Autophagy, a cellular degradation process, is implicated in CS-induced airway damage.

Purpose of the Study:

• To investigate the role of autophagy and HDAC6 in CS-induced cilia dysfunction and MCC disruption in COPD.
• To identify potential therapeutic targets for preserving airway function in COPD.

Main Methods:

• Utilized autophagy-impaired mice (Becn1+/-, Map1lc3B-/-, Hdac6-/Y) and differentiated mouse tracheal epithelial cells (MTECs).
• Exposed mice and MTECs to cigarette smoke (CS) and assessed cilia length, autophagy markers, and MCC.
• Administered HDAC6 inhibitor and chemical chaperone 4-phenylbutyric acid.
• Analyzed human COPD specimens for epigenetic changes in HDAC6.

Main Results:

• CS exposure reduced cilia length and induced autophagy in vivo and in MTECs.
• Autophagy-impaired mice and MTECs were protected from CS-induced cilia shortening.
• CS increased autophagic turnover of ciliary proteins, with HDAC6 identified as a key regulator.
• HDAC6 inhibition or deficiency protected against CS-induced MCC disruption.
• NRF2 deficiency disrupted MCC, suggesting a role for oxidative stress and proteostasis.

Conclusions:

• An autophagy-dependent pathway regulates cilia length during CS exposure in COPD.
• HDAC6 is a critical mediator of autophagy-induced cilia shortening.
• Targeting the autophagy-HDAC6 pathway presents a potential therapeutic strategy for COPD.