Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Molecular and Cellular Biology
Fumiki KatsuokaMasayuki Yamamoto

Abstract

A group of cytoprotective genes is regulated by heterodimers composed of the cap'n'collar (CNC) family member Nrf2 and one of the small Maf (sMaf) proteins (MafF, MafG, or MafK) through the antioxidant response element (ARE, also referred to as the CNC-sMaf binding element [CsMBE]). Many lines of evidence support this model; however, a direct and specific evaluation of the Nrf2-sMaf heterodimer remains to be executed. To address this issue, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide. We then introduced the T-N2G construct into cells lacking all three sMaf proteins to specifically evaluate the function of the tethered heterodimer without interference from other endogenous CNC-sMaf heterodimers or sMaf homodimers. In response to an Nrf2 activator, diethyl maleate, the T-N2G protein can widely activate the target genes of Nrf2 but not those of Nrf1, such as proteasome subunit genes. Genome-wide binding analysis showed that the T-N2G protein preferentially bound to the CsMBE motifs in the regulatory regions of the Nrf2 target genes. These results provide direct evidence that the Nrf2-MafG heterodimer acts as a transcriptional activator of Nrf2-dependent genes and show that this assay sys...Continue Reading

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Citations

Apr 15, 2020·Molecular and Cellular Biology·Liam Baird, Masayuki Yamamoto
Jan 21, 2021·Journal of Cellular and Molecular Medicine·Yan-Qing LiJing Su
Nov 11, 2020·Molecular and Cellular Biology·Akihito OtsukiMasayuki Yamamoto
Jan 7, 2021·Journal of Drug Targeting·Jian-Hong Qi, Fang-Xu Dong
Jun 19, 2021·Journal of Animal Science and Biotechnology·Caiyun HuangFenglai Wang
Jul 3, 2021·Antioxidants·Tabitha Jenkins, Jerome Gouge

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