Abstract
Bicaudal D1 (BICD1), an adaptor for the dynein‐dynactin motor complex, has been identified as a susceptibility gene in chronic obstructive pulmonary disease (COPD). Autophagy, an essential cellular homeostasis process, is defective in COPD, in which oxidative stress‐induced misfolded proteins accumulate into toxic aggregates dependent on the accumulation of the autophagic cargo receptor p62. Defective autophagy can be caused by mutations in the dynein and dynactin motor complex suggesting a possible link between BICD1 and defective autophagy in COPD. BICD1 levels were measured in peripheral lung tissue from COPD patients together with markers of autophagy and found to be increased in COPD together with autophagosomes, p62 and p62 oligomers. In vitro exposure of bronchial epithelial cells to cigarette smoke extracts (CSEs) revealed that high concentrations of CSE induced defective autophagosome maturation with accumulation of BICD1, p62 and ubiquitin‐associated p62 oligomers. This was confirmed in vivo using CS‐exposed mice. Furthermore, we identified that formation of CS‐induced p62 oligomers required an interaction with Keap1. Overexpression and ablation of BICD1 confirmed that increased BICD1 negatively regulates autophagosome maturation inducing accumulation of p62 and p62 oligomers and that it can be reversed by cardiac glycosides. We conclude that defective autophagosome maturation in COPD is caused by oxidative stress‐mediated BICD1 accumulation.
Highlights
Chronic obstructive pulmonary disease (COPD) is an age‐ related condition caused by oxidative stress, usually resulting from long‐term cigarette smoking or biomass smoke exposure that, with no current drugs that can stop the progressive decline in lung function, is set to become the third leading cause of death worldwide.[1]chronic obstructive pulmonary disease (COPD) has been associated with defective turnover of macromolecules damaged by oxidative stress that results in the accumulation of ubiquitinated protein aggregates
Defective autophagic flux could be responsible for Bicaudal D1 (BICD1) accumulation, when BICD1 was knocked down (KD) and cells incubated with increasing concentrations of cigarette smoke extracts (CSEs) (3.3%‐10%), the accumulation of p62 oligomers was decreased as compared to random oligonucleotide control (RO) suggesting that BICD1 is a negative regulator of autophagy (Figure 6C). siRNA treatment increased LC3‐II levels so we used p62 to assess autophagy (Figure 6C)
Defective autophagosome maturation has been associated with the aging of the human vascular system, as demonstrated by accumulation of autophagosomes (LC3‐II) with increased total LC3 levels as well as p62.41 Recently, aggresome bodies have been described in the lung of COPD patients, together with LC3‐II and p62.2,3 We have confirmed that patients suffering from COPD show elevated levels of p62, LC3, and LC3‐II, suggesting that increased presence of autophagosomes is not indicative of high level activation of autophagy but on the contrary, the result of defective autophagosome maturation
Summary
Chronic obstructive pulmonary disease (COPD) is an age‐ related condition caused by oxidative stress, usually resulting from long‐term cigarette smoking or biomass smoke exposure that, with no current drugs that can stop the progressive decline in lung function, is set to become the third leading cause of death worldwide.[1]. Macroautophagy (hereafter referred to as autophagy) is an evolutionary conserved lysosomal degradation process for the elimination and recycling of damaged or surplus cytosolic components This process involves the sequestration of cytoplasmic proteins and organelles into a double membrane vesicle called the autophagosome.[10] During the maturation step, autophagosomes fuse with lysosomes to form autolysosomes, where the final hydrolytic degradation of the engulfed cytoplasmic material takes place.[10] Distinct from the ubiquitin proteasome system (UPS), autophagy can selectively degrade large structures such as protein aggregates, intracellular bacteria, viral capsids, and protein aggregates.[10,11] A more unselective, bulk autophagy process is induced by nutrient limitation. Cardiac glycosides, but not rapamycin, reversed the defective autophagosome maturation
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