한빛사논문
- 조회460
세종대학교
Sang Hyup Lee1,5, Ji-Hye Yang1,5, Ui-Hyun Park2,5, Hanbyeul Choi1, Yoo Sung Kim1, Bo-Eun Yoon1, Hye-Jeong Han3,4, Hyun-Taek Kim3,4, Soo-Jong Um2 and Eun-Joo Kim1
1Department of Molecular Biology, Dankook University, Cheonan 31116, Korea.
2Department of Integrative Bioscience and Biotechnology/Institute of Bioscience, Sejong University, Seoul 143-747, Korea.
3Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 31151 Cheonan-si, Republic of Korea.
4Department of Integrated Biomedical Science, Soonchunhyang University, 31151 Cheonan-si, Republic of Korea.
5These authors contributed equally: Sang Hyup Lee, Ji-Hye Yang, Ui-Hyun Park.
Corresponding authors : Correspondence to Soo-Jong Um or Eun-Joo Kim.
Abstract
SIRT1, a member of the mammalian sirtuin family, is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase with key roles in aging-related diseases and cellular senescence. However, the mechanism by which SIRT1 protein homeostasis is controlled under senescent conditions remains elusive. Here, we revealed that SIRT1 protein is significantly downregulated due to ubiquitin-mediated proteasomal degradation during stress-induced premature senescence (SIPS) and that SIRT1 physically associates with anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase. Ubiquitin-dependent SIRT1 degradation is stimulated by the APC/C coactivator Cdh1 and not by the coactivator Cdc20. We found that Cdh1 depletion impaired the SIPS-promoted downregulation of SIRT1 expression and reduced cellular senescence, likely through SIRT1-driven p53 inactivation. In contrast, AROS, a SIRT1 activator, reversed the SIRT1 degradation induced by diverse stressors and antagonized Cdh1 function through competitive interactions with SIRT1. Furthermore, our data indicate opposite roles for Cdh1 and AROS in the epigenetic regulation of the senescence-associated secretory phenotype genes IL-6 and IL-8. Finally, we demonstrated that pinosylvin restores downregulated AROS (and SIRT1) expression levels in bleomycin-induced mouse pulmonary senescent tissue while repressing bleomycin-promoted Cdh1 expression. Overall, our study provides the first evidence of the reciprocal regulation of SIRT1 stability by APC/C-Cdh1 and AROS during stress-induced premature senescence, and our findings suggest pinosylvin as a potential senolytic agent for pulmonary fibrosis.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-08-22)
- 국내 연구진
- 생명과학 > 분자생물학
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