SIRT6 transcriptionally regulates global protein synthesis through transcription factor Sp1 independent of its deacetylase activity

Author:

Ravi Venkatraman1,Jain Aditi2,Khan Danish1,Ahamed Faiz1,Mishra Sneha1,Giri Malyasree3,Inbaraj Meena1,Krishna Swati1,Sarikhani Mohsen1,Maity Sangeeta1,Kumar Shweta1,Shah Riyaz Ahmad1,Dave Pratik1,Pandit Anwit S1,Rajendran Rajprabu4,Desingu Perumal A1,Varshney Umesh1,Das Saumitra1,Kolthur-Seetharam Ullas5,Rajakumari Sona4,Singh Mahavir36ORCID,Sundaresan Nagalingam R12ORCID

Affiliation:

1. Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India

2. Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India

3. Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India

4. Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India

5. Tata Institute of Fundamental Research, Colaba, Mumbai, India

6. NMR Research Centre, Indian Institute of Science, Bengaluru, India

Abstract

AbstractGlobal 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.

Funder

Department of Biotechnology

Department of Science and Technology

Department of Biotechnology Extramural Research

Publisher

Oxford University Press (OUP)

Subject

Genetics

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