Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China.
Am J Respir Cell Mol Biol. 2020 Oct;63(4):478-489. doi: 10.1165/rcmb.2020-0107OC.
Although endoplasmic reticulum (ER) unfolded protein response (UPR) is well known, mitochondrial unfolded protein response (UPR) has not been recognized in alveolar epithelial cells. Furthermore, ER stress and mitochondrial dysfunction are frequently encountered in alveolar epithelial cells from an array of lung disorders. However, these two scenarios have been often regarded as separate mechanisms contributing to the pathogeneses. It is unclear whether there is interplay between these two phenomena or an integrator that couples these two signaling cascades in the stressed alveolar epithelial cells from those pathologies. In this study, we defined UPR in alveolar epithelial cells and identified ATF4 (activating transcription factor 4), but not ATF5, as the key regulator of UPR. We found that UPR led to UPR and mitochondrial dysfunction in an ATF4-dependent manner. In contrast, mitochondrial stresses did not activate UPR. We found that alveolar epithelial ATF4 and UPR were induced in aged mice with experimental pulmonary fibrosis as well as in patients with idiopathic pulmonary fibrosis. Finally, we found that the inducible expression of ATF4 in mouse alveolar epithelial cells aggravated pulmonary UPR, lung inflammation, body weight loss, and death upon bleomycin-induced lung injury. In conclusion, ER stress induces ATF4-dependent UPR and mitochondrial dysfunction, indicating a novel mechanism by which ER stress contributes to the pathogeneses of a variety of pulmonary disorders.
尽管内质网（ER）未折叠蛋白反应（UPR）广为人知，但在肺泡上皮细胞中尚未发现线粒体未折叠蛋白反应（UPR）。此外，在各种肺部疾病的肺泡上皮细胞中，经常会遇到 ER 应激和线粒体功能障碍。然而，这两种情况通常被视为导致发病机制的两种独立机制。目前尚不清楚这两种现象之间是否存在相互作用，或者在这些病理条件下，应激肺泡上皮细胞中是否存在一种整合因子来偶联这两个信号级联。在这项研究中，我们定义了肺泡上皮细胞中的 UPR，并确定 ATF4（激活转录因子 4），而不是 ATF5，是 UPR 的关键调节因子。我们发现 UPR 以 ATF4 依赖的方式导致 UPR 和线粒体功能障碍。相比之下，线粒体应激不会激活 UPR。我们发现实验性肺纤维化的老年小鼠以及特发性肺纤维化患者的肺泡上皮 ATF4 和 UPR 均被诱导。最后，我们发现小鼠肺泡上皮细胞中 ATF4 的诱导表达加剧了博莱霉素诱导的肺损伤时的肺 UPR、肺炎症、体重减轻和死亡。总之，ER 应激诱导 ATF4 依赖性 UPR 和线粒体功能障碍，表明 ER 应激导致各种肺部疾病发病机制的一种新机制。
