Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan.
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 104-8461, Japan;
J Immunol. 2020 Sep 1;205(5):1256-1267. doi: 10.4049/jimmunol.2000132. Epub 2020 Jul 22.
Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells.
香烟烟雾（CS）会导致错误折叠的蛋白质积累，并随之增强未折叠蛋白反应（UPR）。在慢性阻塞性肺疾病（COPD）发病机制中，已经证明与 UPR 相关的细胞凋亡增加。伴侣介导的自噬（CMA）是溶酶体降解具有 KFERQ 肽基序的蛋白质的一种选择性自噬。CMA 不仅参与维持营养平衡，而且还使细胞适应应激条件。尽管最近的论文表明 UPR 和 CMA 之间存在功能交叉对话，但 CMA 在 COPD 发病机制中的机制意义，特别是与 CS 诱发的 UPR 相关的机制意义仍不清楚。在这项研究中，我们试图使用人支气管上皮细胞（HBEC）和肺组织研究 CMA 在调节 COPD 发病机制中与 UPR 相关的 CS 诱导的细胞凋亡中的作用。CS 提取物（CSE）通过 Nrf2 依赖性方式诱导 HBEC 中的 LAMP2A 表达和 CMA 激活。LAMP2A 敲低和随后的 CMA 抑制增强了 UPR，包括 CHOP 表达，并伴有 CSE 暴露期间细胞凋亡增加，而 LAMP2A 过表达则逆转了这种情况。免疫组织化学显示，与非 COPD 肺相比，COPD 中小气道上皮细胞中的 Nrf2 和 LAMP2A 水平降低。从 COPD 中分离的 HBEC 中 Nrf2 和 LAMP2A 水平均显着降低，而 HBEC 中的 LAMP2A 水平与肺功能测试呈正相关。这些发现表明在 CSE 暴露期间 CMA 和 UPR 之间存在功能交叉对话，并且 CMA 受损可能通过增强上皮细胞中 UPR 介导的细胞凋亡与 COPD 发病机制因果相关。
