SIRT6 transcriptionally regulates global protein synthesis through transcription factor Sp1 independent of its deacetylase activity.
Animals
Cardiomegaly
/ genetics
Gene Expression Regulation
HEK293 Cells
HeLa Cells
Histone Deacetylases
/ genetics
Humans
Mice
Mice, Knockout
Promoter Regions, Genetic
Protein Biosynthesis
Signal Transduction
Sirtuins
/ genetics
Sp1 Transcription Factor
/ chemistry
TOR Serine-Threonine Kinases
/ metabolism
Transcription, Genetic
Zinc Fingers
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
26 09 2019
26 09 2019
Historique:
accepted:
31
07
2019
revised:
30
06
2019
received:
22
10
2018
pubmed:
3
8
2019
medline:
21
12
2019
entrez:
3
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31372634
pii: 5542880
doi: 10.1093/nar/gkz648
pmc: PMC6755095
doi:
Substances chimiques
Sp1 Transcription Factor
0
Sirt6 protein, mouse
EC 2.4.2.31
TOR Serine-Threonine Kinases
EC 2.7.11.1
Sirtuins
EC 3.5.1.-
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9115-9131Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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