SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence
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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.
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.
참고문헌 (56)
- Di Micco, R., "Cellular senescence in ageing : from mechanisms to therapeutic opportunities", Nat. Rev. Mol. Cell Biol, 22, pp.75~95 (2021)
- Campisi, J., "Cellular senescence : when bad things happen to good cells", Nat. Rev. Mol. Cell Biol, 8, pp.729~740 (2007)
- Herranz, N., "Mechanisms and functions of cellular senescence", J. Clin. Invest, 128, pp.1238~1246 (2018)
- Hernandez-Segura, A., "Hallmarks of cellular senescence", Trends Cell Biol, 28, pp.436~453 (2018)
- Coppe, J. P., "Senescence-associated secretory phenotypes reveal cellnonautonomous functions of oncogenic RAS and the p53 tumor suppressor", PLoS Biol, 6, pp.2853~2868 (2008)
- Ben-Porath, I., "The signals and pathways activating cellular senescence", Int. J. Biochem. Cell Biol, 37, pp.961~976 (2005)
- Jung, S. H., "Integrin α6β4-Src-AKT signaling induces cellular senescence by counteracting apoptosis in irradiated tumor cells and tissues", Cell Death Differ, 26, pp.245~259 (2019)
- Lyu, G., "TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging", Nat. Commun, 9, pp.2560~ (2018)
- Childs, B. G., "Cellular senescence in aging and age-related disease: from mechanisms to therapy", Nat. Med, 21, pp.1424~1435 (2015)
- Baker, D. J., "Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan", Nature, 530, pp.184~189 (2016)
- Xu, M., "Senolytics improve physical function and increase lifespan in old age", Nat. Med, 24, pp.1246~1256 (2018)
- Castro, A., "The anaphase-promoting complex : a key factor in the regulation of cell cycle", Oncogene, 24, pp.314~325 (2005)
- Peters, J. M., "The anaphase promoting complex", cyclosome : a machine designed to destroy, 2006, pp.7, 644~656
- Pines, J., "Cubism and the cell cycle : the many faces of the APC", C, 2011, pp.12, 427~438
- Tang, Z., "APC2 cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex", Mol. Biol. Cell, 12, pp.3839~3851 (2001)
- Pfleger, C. M., "Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex", Genes Dev, 15, pp.2396~2407 (2001)
- Fujita, T., "Dissection of the APCCdh1-Skp2cascade in breast cancer", Clin. Cancer Res, 14, pp.1966~1975 (2008)
- Fujita, T., "Regulation of Skp2-p27 axis by the Cdh1", anaphase-promoting complex pathway in colorectal tumorigenesis, 2008, pp.173, 217~228
- Garcia-Higuera, I., "Genomic stability and tumour suppression by the APC", C cofactor Cdh1, 2008, pp.10, 802~811
- Takahashi, A., "DNA damage signaling triggers degradation of histone methyltransferases through APC", C(Cdh1)in senescent cells, 2012, pp.45, 123~131
- Krenning, L., "Transient activation of p53 in G2 phase is sufficient to induce senescence", Mol. Cell, 55, pp.59~72 (2014)
- Johmura, Y., "Necessary and sufficient role for a mitosis skip in senescence induction", Mol. Cell, 55, pp.73~84 (2014)
- Guarente, L., "Sir2 links chromatin silencing, metabolism, and aging", Genes Dev, 14, pp.1021~1026 (2001)
- Smith, J. S., "A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family", Proc. Natl Acad. Sci. USA, 97, pp.6658~6663 (2000)
- Giblin, W., "Sirtuins : guardians of mammalian healthspan", Trends Genet, 30, pp.271~286 (2014)
- Houtkooper, R. H., "Sirtuins as regulators of metabolism and healthspan", Nat. Rev. Mol. Cell Biol, 13, pp.225~238 (2012)
- Peng, L., "Ubiquitinated sirtuin 1(SIRT1)function is modulated during DNA damage-induced cell death and survival", J. Biol. Chem, 290, pp.8904~8912 (2015)
- Kim, M., "CHFR negatively regulates SIRT1 activity upon oxidative stress", Sci. Rep, 6, pp.37578~ (2016)
- Xu, C., "SIRT1 is downregulated by autophagy in senescence and ageing", Nat. Cell Biol, 22, pp.1170~1179 (2020)
- Lin, Z., "USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development", Mol. Cell, 46, pp.484~494 (2012)
- Song, N., "USP7 deubiquitinates and stabilizes SIRT1", Anat. Rec. (Hoboken), 303, pp.1337~1345 (2020)
- Kim, E. J., "Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity", Mol. Cell, 28, pp.277~290 (2007)
- Debacq-Chainiaux, F., "Protocols to detect senescence-associated beta-galactosidase(SA-beta gal)activity, a biomarker of senescent cells in culture and in vivo", Nat. Protoc, 4, pp.1798~1806 (2009)
- Lee, H. K., "MED25 is distinct from TRAP220", MED1 in cooperating with CBP for retinoid receptor activation, 2007, pp.26, 3545~3557
- Back, J. H., "Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin(mTOR)-dependent inhibition of sirtuin 1", J. Biol. Chem, 286, pp.19100~19108 (2011)
- Yao, H., "SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice", J. Clin. Invest, 122, pp.2032~2045 (2012)
- Tran, D., "Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence", Aging Cell, 13, pp.6696~6678 (2014)
- Chang, L., "Molecular architecture and mechanism of the anaphase-promoting complex", Nature, 513, pp.388~393 (2014)
- Hayakawa, T., "SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation", PLoS ONE, 10, pp.e0116480~ (2015)
- Jang, M. J., "CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγand inhibit adipogenesis", Cell Death Dis, 8, pp.3201~ (2017)
- Kellogg, D. L., "Cellular senescence in idiopathic pulmonary fibrosis", Curr. Mol. Biol. Rep, 12, pp.1~10 (2021)
- Schafer, M. J., "Cellular senescence mediates fibrotic pulmonary disease", Nat. Commun, 8, pp.14532~ (2017)
- Chu, H., "Sirtuin1 protects against systemic sclerosis-related pulmonary fibrosis by decreasing proinflammatory and profibrotic processes", Am. J. Respir. Cell Mol. Biol, 58, pp.28~39 (2018)
- Mazumder, S., "Sirtuins as endogenous regulators of lung fibrosis : a current perspective", Life Sci, 258, pp.118201~ (2020)
- Modi, S., "Plant-derived compounds strigolactone GR24 and pinosylvin activate SIRT1 and enhance glucose uptake in rat skeletal muscle cells", Sci. Rep, 7, pp.17606~ (2017)
- Modi, S., "Strigolactone GR24 and pinosylvin attenuate adipogenesis and inflammation of white adipocytes", Biochem. Biophys. Res. Commun, 499, pp.164~169 (2018)
- Aoshiba, K., "Bleomycin induces cellular senescence in alveolar epithelial cells", Eur. Respir. J, 22, pp.436~443 (2003)
- Mouratis, M. A., "Modeling pulmonary fibrosis with bleomycin", Curr. Opin. Pulm. Med, 17, pp.355~361 (2011)
- Yu, L., "Ubiquitination-mediated degradation of SIRT1 by SMURF2 suppresses CRC cell proliferation and tumorigenesis", Oncogene, 39, pp.4450~4464 (2020)
- Liu, P. Y., "E3 ubiquitin ligase Grail promotes hepatic steatosis through Sirt1inhibition", Cell Death Dis, 12, pp.323~ (2021)
- Zhang, J., "Functional characterization of anaphase promoting complex", cyclosome(APC, Biochim. Biophys. Acta, pp.2014, 1845[DOI]
- Kim, H. S., "SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC", C activity, 2011, pp.20, 487~499
- Wang, H., "Reciprocal interaction between SIRT6 and APC", C regulates genomic stability, 2021, pp.11, 14253~
- Zhang, W., "SIRT1 modulates cell cycle progression by regulating CHK2acetylation-phosphorylation", Cell Death Differ, 27, pp.482~496 (2020)
- Ling, H., "Histone deacetylase SIRT1 targets Plk2 to regulate centriole duplication", Cell Rep, 25, pp.2851~2865 (2018)
- Wiebusch, L., "p53-and p21-dependent premature APC", C-Cdh1activation in G2 is part of the long-term response to genotoxic stress, 2010, pp.29, 3477~3489