Bicaudal D1 impairs autophagosome maturation in chronic obstructive pulmonary disease
Bicaudal D1 impairs autophagosome maturation in chronic obstructive pulmonary disease
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DOI：
10.1096/fba.2018-00055
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发表时间：
2019-11-01
影响因子：
2.7
通讯作者：
Barnes, Peter J.
中科院分区：
文献类型：
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作者：
Mercado, Nicolas;Colley, Thomas;Barnes, Peter J.
作为动力蛋白-动力蛋白复合体的接头基因，Bicaudal D_1(BICD_1)被认为是慢性阻塞性肺疾病(COPD)的易感基因。自噬是一种重要的细胞内稳态过程，在COPD中是有缺陷的，在COPD中，氧化应激诱导的错误折叠的蛋白质依赖于自噬货物受体p62的积累积累成有毒的聚集体。自噬缺陷可由动力蛋白和动力蛋白运动复合体的突变引起，提示BICD1可能与COPD的自噬缺陷有关。通过检测COPD患者外周肺组织中BICD1水平和自噬标志物，发现COPD患者外周肺组织中BICD1水平与自噬小体、p62和p62寡聚体一起增加。体外培养的支气管上皮细胞暴露于香烟烟雾提取物(CSE)后，发现高浓度CSE可诱导有缺陷的自噬小体成熟，并积聚BICD1、p62和泛素相关的p62寡聚体。这在体内用暴露于CS的小鼠进行了证实。此外，我们发现CS诱导的p62寡聚体的形成需要与Keap1相互作用。BICD 1的过表达和消融证实，BICD 1的增加负性调节自噬小体成熟，诱导p62和p62寡聚体的积聚，并且这种作用可以被心苷类药物逆转。我们得出结论，COPD患者自噬小体成熟缺陷是由氧化应激介导的BICD1积聚引起的。
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.