Ravi, V and Jain, A and Khan, D and Ahamed, F and Mishra, S and Giri, M and Inbaraj, M and Krishna, S and Sarikhani, M and Maity, S and Kumar, S and Shah, RA and Dave, P and Pandit, AS and Rajendran, R and Desingu, PA and Varshney, U and Das, S and Kolthur-Seetharam, U and Rajakumari, S and Singh, M and Sundaresan, NR (2019) SIRT6 transcriptionally regulates global protein synthesis through transcription factor Sp1 independent of its deacetylase activity. In: Nucleic Acids Research, 47 (17). pp. 9115-9131.
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Abstract
Global protein synthesis is emerging as an important player in the context of aging and age-related diseases. However, the intricate molecular networks that regulate protein synthesis are poorly understood. Here, we report that SIRT6, a nuclear-localized histone deacetylase represses global protein synthesis by transcriptionally regulating mTOR signalling via the transcription factor Sp1, independent of its deacetylase activity. Our results suggest that SIRT6 deficiency increases protein synthesis in mice. Further, multiple lines of in vitro evidence suggest that SIRT6 negatively regulates protein synthesis in a cell-autonomous fashion and independent of its catalytic activity. Mechanistically, SIRT6 binds to the zinc finger DNA binding domain of Sp1 and represses its activity. SIRT6 deficiency increased the occupancy of Sp1 at key mTOR signalling gene promoters resulting in enhanced expression of these genes and activation of the mTOR signalling pathway. Interestingly, inhibition of either mTOR or Sp1 abrogated the increased protein synthesis observed under SIRT6 deficient conditions. Moreover, pharmacological inhibition of mTOR restored cardiac function in muscle-specific SIRT6 knockout mice, which spontaneously develop cardiac hypertrophy. Overall, these findings have unravelled a new layer of regulation of global protein synthesis by SIRT6, which can be potentially targeted to combat aging-associated diseases like cardiac hypertrophy. © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
| Item Type: | Journal Article |
|---|---|
| Publication: | Nucleic Acids Research |
| Publisher: | Oxford University Press |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | histone deacetylase; mammalian target of rapamycin; sirtuin 6; transcription factor Sp1; histone deacetylase; Sirt6 protein, mouse; sirtuin; target of rapamycin kinase; transcription factor Sp1; zinc finger protein, animal experiment; animal model; animal tissue; Article; catalysis; controlled study; DNA binding motif; enzyme activity; enzyme repression; gene expression; heart function; heart ventricle hypertrophy; human; human cell; in vitro study; mouse; mTOR signaling; nonhuman; priority journal; promoter region; protein DNA binding; protein synthesis; transcription regulation; animal; cardiomegaly; chemistry; gene expression regulation; genetic transcription; genetics; HEK293 cell line; HeLa cell line; knockout mouse; metabolism; signal transduction, Animals; Cardiomegaly; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Histone Deacetylases; Humans; Mice; Mice, Knockout; Promoter Regions, Genetic; Protein Biosynthesis; Signal Transduction; Sirtuins; Sp1 Transcription Factor; TOR Serine-Threonine Kinases; Transcription, Genetic; Zinc Fingers |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Molecular Reproduction, Development & Genetics Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility) Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering |
| Date Deposited: | 13 Oct 2022 05:34 |
| Last Modified: | 13 Oct 2022 05:34 |
| URI: | https://eprints.iisc.ac.in/id/eprint/77351 |
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