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FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping.

Authors
  • Wang, Lihui1
  • Chen, Ruping1
  • Li, Guo1
  • Wang, Zhiguo1
  • Liu, Jun1
  • Liang, Ying1
  • Liu, Jun-Ping2
  • 1 Institute of Ageing Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China. , (China)
  • 2 Institute of Ageing Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China; Hangzhou Duanli Biotechnology Company Limited, Hangzhou, Zhejiang Province 311121, China; Department of Immunology, Monash University Faculty of Medicine, Prahran, VIC 3181, Australia; Hudson Institute of Medical Research, and Monash University Department of Molecular and Translational Science, Clayton, VIC 3168, Australia. Electronic address: [email protected] , (Australia)
Type
Published Article
Journal
Cell metabolism
Publication Date
Oct 14, 2020
Identifiers
DOI: 10.1016/j.cmet.2020.10.004
PMID: 33086033
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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 β 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. Copyright © 2020 Elsevier Inc. All rights reserved.

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