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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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Sirt6 mediates antioxidative functions by increasing Nrf2 abundance

Xiuzhen Liu1, Sichong Ren2, Zuozhi Li3

  • 1State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, PR China; Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China.

Experimental Cell Research
|November 10, 2022
PubMed

Insights

Sirtuin 6 (Sirt6) enhances the protective Nrf2 antioxidant response by stabilizing Nrf2 protein levels, thereby mitigating oxidative stress and improving survival in mice.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Oxidative stress from reactive oxygen species (ROS) causes cellular damage.
  • Sirtuin 6 (Sirt6), a NAD+-dependent deacetylase, regulates cellular processes and exhibits antioxidative functions.
  • Sirt6's role in regulating the Nrf2 antioxidant pathway requires further elucidation.

Purpose of the Study:

  • To investigate the role of Sirt6 in regulating oxidative stress responses.
  • To determine the mechanism by which Sirt6 influences the Nrf2 pathway.
  • To assess the impact of Sirt6 on cellular and organismal responses to oxidative insults.

Main Methods:

  • Induction of Sirt6 expression using hydrogen peroxide (H2O2) and paraquat (PQ).
  • Phenotypic analysis of Sirt6-deficient (Sirt6+/-) and wild-type (Sirt6+/+) mice exposed to PQ.
  • Western blot and RT-qPCR to measure Nrf2 protein and target gene mRNA levels.
  • Co-immunoprecipitation (Co-IP) and GST pull-down assays to study protein interactions.

Main Results:

  • Sirt6 expression was induced by H2O2 and PQ.
  • Sirt6 deficiency exacerbated PQ-induced liver damage and reduced survival in mice.
  • Sirt6 deficiency decreased Nrf2 protein and target gene expression, while Sirt6 overexpression increased Nrf2 levels.
  • Sirt6 enhanced Nrf2 nuclear accumulation and stability, and reduced Nrf2-Keap1 binding.

Conclusions:

  • Sirt6 plays a critical role in protecting against oxidative stress.
  • Sirt6 enhances the Nrf2 antioxidant response by stabilizing Nrf2 protein via the Keap1-mediated pathway.
  • Sirt6 represents a potential therapeutic target for combating oxidative stress-related diseases.
Keywords:
AntioxidantKeap1Nrf2Sirt6

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