Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease
Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease
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DOI：
10.1165/rcmb.2016-0198oc
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发表时间：
2017-01-01
影响因子：
6.4
通讯作者：
Rahman, Irfan
中科院分区：
文献类型：
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作者：
Ahmad, Tanveer;Sundar, Isaac K.;Rahman, Irfan
肺细胞衰老和炎症反应是慢性阻塞性肺疾病（COPD）发病的关键事件，其中香烟烟雾（CS）是主要病因。端粒功能障碍是由庇护蛋白复合物的严重缩短或破坏引起的，导致细胞衰老。然而，尚不清楚遮蔽蛋白复合物的破坏是否与cs诱导的肺细胞衰老有关。在这里，我们发现端粒保护蛋白1 （TPP1）水平在肺气肿小鼠、吸烟者和COPD患者的肺端粒中降低。这与持续的端粒DNA损伤有关，导致细胞衰老。CS破坏TPP1与Sirt1复合物的相互作用，导致TPP1乙酰化和降解增加。缺乏Sirt1或用选择性Sirt1抑制剂处理的肺成纤维细胞表现出细胞衰老增加和TPP1水平降低，而Sirt1过表达和药理激活可防止cs诱导的TPP1减少和端粒DNA损伤。我们的研究结果支持TPP1在保护cs诱导的端粒DNA损伤和细胞衰老方面的重要作用，因此为基于庇护蛋白复合物减缓细胞衰老的COPD潜在治疗提供了理论依据。
Lung cellular senescence and inflammatory response are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) when cigarette smoke (CS) is the main etiological factor. Telomere dysfunction is induced by either critical shortening or disruption of the shelterin complex, leading to cellular senescence. However, it remains unknown whether disruption of the shelterin complex is responsible for CS-induced lung cellular senescence. Here we show that telomere protection protein 1 (TPP1) levels are reduced on telomeres in lungs from mice with emphysema, as well as in lungs from smokers and from patients with COPD. This is associated with persistent telomeric DNA damage, leading to cellular senescence. CS disrupts the interaction of TPP1 with the Sirtuin 1 (Sirt1) complex, leading to increased TPP1 acetylation and degradation. Lung fibroblasts deficient in Sirt1 or treated with a selective Sirt1 inhibitor exhibit increased cellular senescence and decreased TPP1 levels, whereas Sirt1 overexpression and pharmacological activation protect against CS-induced TPP1 reduction and telomeric DNA damage. Our findings support an essential role of TPP1 in protecting CS-induced telomeric DNA damage and cellular senescence, and therefore provide a rationale for a potential therapy for COPD, on the basis of the shelterin complex, in attenuating cellular senescence.