SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-06-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-01012-1 |
| _version_ | 1827905583316992000 |
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| author | Sang Hyup Lee Ji-Hye Yang Ui-Hyun Park Hanbyeul Choi Yoo Sung Kim Bo-Eun Yoon Hye-Jeong Han Hyun-Taek Kim Soo-Jong Um Eun-Joo Kim |
| author_facet | Sang Hyup Lee Ji-Hye Yang Ui-Hyun Park Hanbyeul Choi Yoo Sung Kim Bo-Eun Yoon Hye-Jeong Han Hyun-Taek Kim Soo-Jong Um Eun-Joo Kim |
| author_sort | Sang Hyup Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T00:44:30Z |
| format | Article |
| id | doaj.art-616241520e48488abcffd5f96b594298 |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-03-13T00:44:30Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-616241520e48488abcffd5f96b5942982023-07-09T11:07:35ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-06-015561232124610.1038/s12276-023-01012-1SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescenceSang Hyup Lee0Ji-Hye Yang1Ui-Hyun Park2Hanbyeul Choi3Yoo Sung Kim4Bo-Eun Yoon5Hye-Jeong Han6Hyun-Taek Kim7Soo-Jong Um8Eun-Joo Kim9Department of Molecular Biology, Dankook UniversityDepartment of Molecular Biology, Dankook UniversityDepartment of Integrative Bioscience and Biotechnology/Institute of Bioscience, Sejong UniversityDepartment of Molecular Biology, Dankook UniversityDepartment of Molecular Biology, Dankook UniversityDepartment of Molecular Biology, Dankook UniversitySoonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang UniversitySoonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang UniversityDepartment of Integrative Bioscience and Biotechnology/Institute of Bioscience, Sejong UniversityDepartment of Molecular Biology, Dankook UniversityAbstract 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.https://doi.org/10.1038/s12276-023-01012-1 |
| spellingShingle | Sang Hyup Lee Ji-Hye Yang Ui-Hyun Park Hanbyeul Choi Yoo Sung Kim Bo-Eun Yoon Hye-Jeong Han Hyun-Taek Kim Soo-Jong Um Eun-Joo Kim SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence Experimental and Molecular Medicine |
| title | SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence |
| title_full | SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence |
| title_fullStr | SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence |
| title_full_unstemmed | SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence |
| title_short | SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence |
| title_sort | sirt1 ubiquitination is regulated by opposing activities of apc c cdh1 and aros during stress induced premature senescence |
| url | https://doi.org/10.1038/s12276-023-01012-1 |
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