"Ciliophagy": The consumption of cilia components by autophagy

Abstract

Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) associated with respiratory epithelial cell cilia shortening and impaired mucociliary clearance (MCC). The underlying cellular and molecular mechanisms for CS-associated cilia shortening have remained incompletely understood. We have previously demonstrated increased autophagy in the lungs of COPD patients; however, whether or not this process is selective for specific autophagic targets in the lung was not elucidated. Based on observations that increased morphological and biochemical indicators of autophagy correlate with cilia shortening in our models, we posited that autophagy might regulate cilia length in response to CS in the lung. We demonstrate that CS-induced cilia shortening occurs through an autophagy-dependent mechanism mediated by the deacetylase HDAC6 (histone deacetylase 6). Autophagy-impaired (Becn1(+/-), map1lc3b(-/-), or Hdac6(-/Y)) mice resist CS-induced cilia shortening. Furthermore, cilia components are identified as autophagic substrates during CS exposure. Assessment of airway cilia function using a 3D MCC assay demonstrates that Becn1(+/-), map1lc3b(-/-), and Hdac6(-/Y) mice or mice injected with the HDAC6 inhibitor tubastatin A are protected from CS-associated mucociliary dysfunction. We concluded that an autophagy-dependent pathway regulates cilia length during CS exposure, which identifies new pathways and targets in COPD.

Keywords: COPD; HDAC6; autophagy; cilia; lung.

Figure 1. Ciliophagy and COPD. The mucociliary escalator covers most of the bronchi, bronchioles, and nose. It is composed of mucus-producing goblet cells and the ciliated epithelium (left). The cilia are constantly beating, pushing mucus up and out into the throat (center). Cigarette smoke induces oxidative stress, which leads to cilia protein damage, misfolding, ubiquitination, and the formation of intracellular protein aggregates (right). HDAC6 recognizes ubiquitinated protein aggregates and delivers them to the autophagosome. Cilia proteins are subsequently delivered to the lysosome for degradation or recycling. In cases of chronic oxidative stress, cilia proteins are degraded resulting in the shortening of airway cilia contributing to impaired mucociliary clearance (right). Genetic deletion of LC3B (map1lc3b), BECN1 (Becn1) or HDAC6 (Hdac6) or inhibiting 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.