Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan;
J Immunol. 2019 Mar 1;202(5):1428-1440. doi: 10.4049/jimmunol.1801293. Epub 2019 Jan 28.
Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain-containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1β-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.
核层蛋白 B1 的下调已被认为是完全衰老发展的关键步骤。与雷帕霉素靶蛋白激酶 (mTOR) 信号转导和线粒体损伤积累相关的加速细胞衰老已被牵连到慢性阻塞性肺疾病 (COPD) 的发病机制中。我们假设核层蛋白 B1 的蛋白水平在 COPD 肺中降低，通过 mTOR 和线粒体完整性的失调导致香烟烟雾 (CS) 诱导的细胞衰老过程。为了阐明核层蛋白 B1 在 COPD 发病机制中的作用，我们评估了 CS 提取物 (CSE) 处理的人支气管上皮细胞 (HBEC)、CS 暴露的小鼠和 COPD 肺中的核层蛋白 B1 蛋白水平、mTOR 激活、线粒体质量和细胞衰老。我们表明，暴露于 CSE 会降低核层蛋白 B1 的水平，自噬是 HBEC 中核层蛋白 B1 降解的原因。核层蛋白 B1 的减少与 mTOR 激活有关，通过 DEP 结构域包含 mTOR 相互作用蛋白 (DEPTOR) 的下调导致细胞衰老加速。异常的 mTOR 激活与增加的线粒体质量有关，这可归因于过氧化物酶体增殖物激活受体 γ 共激活因子-1β 介导的线粒体生物发生。CS 暴露的小鼠肺和 COPD 肺也显示出核层蛋白 B1 和 DEPTOR 蛋白水平降低，同时伴有 mTOR 激活，伴有增加的线粒体质量和细胞衰老。抗糖尿病二甲双胍通过增加 DEPTOR 的表达来预防 CSE 诱导的 HBEC 衰老和线粒体积累。这些发现表明，核层蛋白 B1 的减少不仅是肺部衰老的标志，而且还通过异常的 mTOR 信号参与 COPD 发病机制中细胞衰老的进展。
