Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China.
Research Unit of Respiratory Disease, Central South University, Changsha, China.
Cell Death Dis. 2023 Sep 19;14(9):614. doi: 10.1038/s41419-023-06131-1.
Ovarian tumor family deubiquitinase 4 (OTUD4), a member of the OTU deubiquitinating enzyme, is implicated to decrease in cancer to regulate cell apoptosis. However, the role of OTUD4 in cigarette smoke induced epithelial cell apoptosis and its mechanism have not been elucidated. In this study, we showed that OTUD4 protein reduced in CSE treated mice and airway epithelial cells. OTUD4 silence aggravated cell apoptosis and emphysematous change in the lung tissue of cigarette smoke extract (CSE) treated mice. Additionally, restoration of OTUD4 in the lung of mice alleviated CSE induced apoptosis and emphysematous morphology change. The effect of OTUD4 on cell apoptosis was also confirmed in vitro. Through protein profile screening, we identified that OTUD4 may interact with plasminogen activator inhibitor 1(PAI-1). We further confirmed that OTUD4 interacted with PAI-1 for de-ubiquitination and inhibiting CSE induced PAI-1 degradation. Furthermore, the protective role of OTUD4 in airway epithelial cells apoptosis was blocked by PAI-1 deactivation. Taken together, our data suggest that OTUD4 regulates cigarette smoke (CS)-triggered airway epithelial cell apoptosis via modulating PAI-1 degradation. Targeting OUTD4/PAI-1 signaling might potentially provide a therapeutic target against the lung cell apoptosis in cigarette smoke (CS)-induced emphysema.
卵巢肿瘤家族去泛素化酶 4（OTUD4）是 OTU 去泛素化酶的成员，据报道在癌症中减少以调节细胞凋亡。然而，OTUD4 在香烟烟雾诱导的上皮细胞凋亡中的作用及其机制尚未阐明。在这项研究中，我们表明 CSE 处理的小鼠和气道上皮细胞中 OTUD4 蛋白减少。OTUD4 沉默加剧了香烟烟雾提取物（CSE）处理的小鼠肺组织中的细胞凋亡和肺气肿变化。此外，在小鼠肺部恢复 OTUD4 可减轻 CSE 诱导的细胞凋亡和肺气肿形态变化。OTUD4 对细胞凋亡的影响也在体外得到了证实。通过蛋白质谱筛选，我们发现 OTUD4 可能与纤溶酶原激活物抑制剂 1（PAI-1）相互作用。我们进一步证实，OTUD4 与 PAI-1 相互作用以进行去泛素化，并抑制 CSE 诱导的 PAI-1 降解。此外，OTUD4 对气道上皮细胞凋亡的保护作用被 PAI-1 失活所阻断。总之，我们的数据表明，OTUD4 通过调节 PAI-1 降解来调节香烟烟雾（CS）触发的气道上皮细胞凋亡。靶向 OUTD4/PAI-1 信号可能为治疗香烟烟雾（CS）诱导的肺气肿中的肺细胞凋亡提供潜在的治疗靶点。
