European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy.
Autophagy. 2011 Jan;7(1):104-6. doi: 10.4161/auto.7.1.13987. Epub 2011 Jan 1.
The accumulation of misfolded and/or ubiquitinated protein aggregates with a perturbation of autophagy has been described in several human pathologies. A sequestration of misfolded cystic: fibrosis transmembrane conductance regulator (CFTR) and cross-linked PPARγ has been observed in airway epithelia of cystic fibrosis (CF) patients. CF airways are also characterized by chronic inflammation, pro-oxidative environment and increased transglutaminase 2 (TG2) levels. We showed that defective CFTR drives autophagy inhibition through reactive oxygen species (ROS)-TG2- mediated aggresome sequestration of the Beclin 1 interactome. Rescuing Beclin 1 at the level of the endoplasmic reticulum and autophagy favors clearance of aggresomes, improves CFTR trafficking and ameliorates CF lung inflammation both in vitro and in vivo. Therefore, rescuing autophagy interrupts the vicious cycle linking defective CFTR and lung inflammation and may pave the way to the development of a novel class of drugs for the treatment of CF.
在几种人类疾病中，已经描述了错误折叠和/或泛素化蛋白聚集体的积累，以及自噬的扰动。在囊性纤维化 (CF) 患者的气道上皮中，已经观察到错误折叠的囊性纤维化跨膜电导调节因子 (CFTR) 和交联的过氧化物酶体增殖物激活受体 γ (PPARγ) 的隔离。CF 气道还具有慢性炎症、促氧化环境和转谷氨酰胺酶 2 (TG2) 水平升高的特点。我们表明，有缺陷的 CFTR 通过活性氧 (ROS)-TG2 介导的 Beclin 1 相互作用体聚集体隔离来驱动自噬抑制。在内质网水平和自噬水平上拯救 Beclin 1，有利于聚集体的清除，改善 CFTR 运输，并改善体外和体内 CF 肺炎症。因此，挽救自噬中断了有缺陷的 CFTR 和肺炎症之间的恶性循环，并可能为治疗 CF 的新型药物的开发铺平道路。
