FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping
FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping
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FBW7 通过端粒脱帽介导衰老和肺纤维化
DOI：
10.1016/j.cmet.2020.10.004
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发表时间：
2020-11-03
期刊：
影响因子：
29
通讯作者：
Liu, Jun-Ping
中科院分区：
文献类型：
--
作者：
Wang, Lihui;Chen, Ruping;Liu, Jun-Ping
组织干细胞在压力下过早衰老，促进与年龄有关的疾病；然而，相关机制尚不清楚。在这里，我们报道了在辐射、氧化应激或博来霉素的作用下，E3泛素连接酶FBW7通过端粒脱帽介导细胞衰老和组织纤维化。FBW7与端粒保护蛋白1 （TPP1）结合，促进TPP1多点多泛素化，加速降解，触发端粒脱帽和DNA损伤反应。过表达TPP1或通过基因消融、表观遗传干扰或模拟肽端粒功能障碍抑制剂（TELODIN）抑制FBW7可减少端粒脱帽和缩短，扩大小鼠肺泡AEC2干细胞群。TELODIN由FBW7 WD40螺旋桨结构域的第7条b链叶片合成，可提高长期环境应激动物TPP1的稳定性、肺呼吸功能以及抗衰老和纤维化能力。我们的研究结果阐明了应激诱导的肺上皮干细胞衰老和纤维化的关键机制，为衰老相关疾病的干预提供了一个框架。
Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh b strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.