Sirt6 mediates antioxidative functions by increasing Nrf2 abundance

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.