Regulation of the NRF2 Transcription Factor Activity Via SIRT1-Induced Deacetylation: Possible SIRT1–NRF2 Feedback Loop

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Abstract

NRF2 is a key component that is associated with protecting cells from damage. It is intersected by other signaling pathways that can have both direct and indirect effects on it. Proteins that can influence activity through acetylation and deacetylation, such as p300/CBP, HDACs and SIRT1, play an important role in these signaling pathways. But sometimes the research of different scientific groups contradict each other. On the one hand, there is evidence showing that acetylation increases the activity of NRF2, while deacetylation reduces the activity and level of transcripts of genes regulated by NRF2. On the other hand, some results show that activation of SIRT1 deacetylase increases the posttranslational activity of NRF2. At the same time, NRF2 itself affects the expression of SIRT1, forming a positive feedback loop. This review examines various aspects of the interaction between the activity of transcription factor NRF2 and acetylases/deacetylases, primarily SIRT1. In addition, variants of indirect interaction between NRF2 and SIRT1 through other signaling pathways associated with proteins such as PGC-1α and p62 are being considered.

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About the authors

A. P. Gureev

Voronezh State University; Voronezh State University of Engineering Technologies

Email: kru751@rambler.ru
Russian Federation, Voronezh, 394018; Voronezh, 394036

E. P. Krutskikh

Voronezh State University

Author for correspondence.
Email: kru751@rambler.ru
Russian Federation, Voronezh, 394018

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2. Fig. 1. Predicted binding sites of SIRT1 to NRF2, which range from 12 tpn to the transcription initiation point (TSS). At the top of the squares is the (+) sequence of the potential ARE, at the bottom is the (−) sequence.

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3. 2. The effect of acetylases (marked in red) and deacetylases (marked in yellow) on the activity of the NRF2 transcription factor. Potential regulation of SIRT1 gene expression by NRF2 has been noted. It has been shown that SIRT1 can deacetylate PGC-1a and p62, which inhibit GSK3b and KEAP1 and therefore activate NRF2.Thus, SIRT1 can participate in the regulation of NRF2 activity both directly and indirectly.

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