C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress.
FoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4--homolog of mammalian SIRT6 and SIRT7 proteins--promotes DAF-16-dependent transcription and stress-...
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| Language: | English |
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Public Library of Science (PLoS)
2012-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002948&type=printable |
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| author | Wei-Chung Chiang Daniel X Tishkoff Bo Yang Joshua Wilson-Grady Xiaokun Yu Travis Mazer Mark Eckersdorff Steven P Gygi David B Lombard Ao-Lin Hsu |
| author_facet | Wei-Chung Chiang Daniel X Tishkoff Bo Yang Joshua Wilson-Grady Xiaokun Yu Travis Mazer Mark Eckersdorff Steven P Gygi David B Lombard Ao-Lin Hsu |
| author_sort | Wei-Chung Chiang |
| collection | DOAJ |
| description | FoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4--homolog of mammalian SIRT6 and SIRT7 proteins--promotes DAF-16-dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF-16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function. |
| format | Article |
| id | doaj-art-bb004d8048fb42b5bcb34cc75542201d |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2012-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-bb004d8048fb42b5bcb34cc75542201d2025-08-20T03:26:42ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-09-0189e100294810.1371/journal.pgen.1002948C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress.Wei-Chung ChiangDaniel X TishkoffBo YangJoshua Wilson-GradyXiaokun YuTravis MazerMark EckersdorffSteven P GygiDavid B LombardAo-Lin HsuFoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4--homolog of mammalian SIRT6 and SIRT7 proteins--promotes DAF-16-dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF-16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002948&type=printable |
| spellingShingle | Wei-Chung Chiang Daniel X Tishkoff Bo Yang Joshua Wilson-Grady Xiaokun Yu Travis Mazer Mark Eckersdorff Steven P Gygi David B Lombard Ao-Lin Hsu C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. PLoS Genetics |
| title | C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. |
| title_full | C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. |
| title_fullStr | C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. |
| title_full_unstemmed | C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. |
| title_short | C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. |
| title_sort | c elegans sirt6 7 homolog sir 2 4 promotes daf 16 relocalization and function during stress |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002948&type=printable |
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