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FBW7通过端粒脱帽来介导衰老和肺纤维化
作者:小柯机器人 发布时间:2020/10/24 21:50:01

杭州师范大学刘俊平研究团队发现,FBW7通过端粒脱帽来介导衰老和肺纤维化。这一研究成果于2020年10月20日在线发表在国际学术期刊《细胞—代谢》上。

研究人员发现,响应辐射、氧化应激或博来霉素时,E3泛素连接酶FBW7通过端粒脱帽来介导细胞衰老和组织纤维化。FBW7与端粒保护蛋白1(TPP1)的结合促进TPP1多位点多聚泛素化并加速降解,进而触发端粒脱帽和DNA损伤反应。TPP1过表达或者通过基因敲除、表观遗传干扰或拟肽端粒功能障碍抑制因子(TELODIN)来抑制FBW7,可以减少端粒的脱帽和缩短,从而扩大小鼠肺泡AEC2干细胞群体。TELODIN是由FBW7 WD40螺旋桨域的第七个β链叶片合成的,可增加TPP1的稳定性、肺呼吸功能以及对长期暴露于环境压力动物的衰老和纤维化的抵抗力。
 
这些发现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框架。
 
据介绍,组织干细胞在压力下会过早衰老,从而促进与年龄有关的疾病;但是,相关机制仍不清楚。
 
附:英文原文

Title: FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping

Author: Lihui Wang, Ruping Chen, Guo Li, Zhiguo Wang, Jun Liu, Ying Liang, Jun-Ping Liu

Issue&Volume: 2020-10-21

Abstract: Tissue stem cells undergo premature senescence under stress, promoting age-relateddiseases; however, the associated mechanisms remain unclear. Here, we report thatin response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligaseFBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitinationand 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 uncappingand shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice.TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain,increases TPP1 stability, lung respiratory function, and resistance to senescenceand fibrosis in animals chronically exposed to environmental stress. Our findingselucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stemcell senescence and fibrosis, providing a framework for aging-related disorder interventions.

DOI: 10.1016/j.cmet.2020.10.004

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30537-4

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx