Department of Internal Medicine, Justus-Liebig University, Giessen, Germany; Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Germany;
Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; REBIRTH Cluster of Excellence, Hannover, Germany;
Am J Physiol Lung Cell Mol Physiol. 2016 Mar 15;310(6):L519-31. doi: 10.1152/ajplung.00213.2015. Epub 2015 Dec 30.
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, and some patients with HPS develop pulmonary fibrosis, known as HPS-associated interstitial pneumonia (HPSIP). We have previously reported that HPSIP is associated with severe surfactant accumulation, lysosomal stress, and alveolar epithelial cell type II (AECII) apoptosis. Here, we hypothesized that defective autophagy might result in excessive lysosomal stress in HPSIP. Key autophagy proteins, including LC3B lipidation and p62, were increased in HPS1/2 mice lungs. Electron microscopy demonstrated a preferable binding of LC3B to the interior of lamellar bodies in the AECII of HPS1/2 mice, whereas in wild-type mice it was present on the limiting membrane in addition to the interior of the lamellar bodies. Similar observations were noted in human HPS1 lung sections. In vitro knockdown of HPS1 revealed increased LC3B lipidation and p62 accumulation, associated with an increase in proapoptotic caspases. Overexpression of LC3B decreased the HPS1 knockdown-induced p62 accumulation, whereas rapamycin treatment did not show the same effect. We conclude that loss of HPS1 protein results in impaired autophagy that is restored by exogenous LC3B and that defective autophagy might therefore play a critical role in the development and progression of HPSIP.
Hermansky-Pudlak 综合征（HPS）是一种罕见的常染色体隐性遗传病，一些 HPS 患者会发展为肺纤维化，称为 HPS 相关间质性肺炎（HPSIP）。我们之前曾报道 HPSIP 与严重的表面活性剂积累、溶酶体应激和肺泡上皮细胞 II 型（AECII）凋亡有关。在这里，我们假设缺陷的自噬可能导致 HPSIP 中溶酶体应激过度。关键的自噬蛋白，包括 LC3B 脂质化和 p62，在 HPS1/2 小鼠的肺部中增加。电子显微镜显示，HPS1/2 小鼠的 AECII 中 LC3B 与板层小体的内部更好地结合，而在野生型小鼠中，LC3B 除了板层小体的内部之外，还存在于其限界膜上。在人类 HPS1 肺切片中也观察到了类似的发现。体外敲低 HPS1 显示 LC3B 脂质化和 p62 积累增加，与促凋亡半胱天冬酶增加有关。LC3B 的过表达减少了 HPS1 敲低诱导的 p62 积累，而雷帕霉素处理则没有相同的效果。我们得出结论，HPS1 蛋白的缺失导致自噬受损，外源性 LC3B 可使其恢复，因此缺陷的自噬可能在 HPSIP 的发生和进展中起关键作用。
