Target Gene Diversity of the Nrf1-MafG Transcription Factor Revealed by a Tethered Heterodimer
Target Gene Diversity of the Nrf1-MafG Transcription Factor Revealed by a Tethered Heterodimer
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DOI：
10.1128/mcb.00520-21
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发表时间：
2022-03-17
影响因子：
5.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Katsuoka, Fumiki;Otsuki, Akihito;Yamamoto, Masayuki
转录因子的帽环（CNC）家族成员，包括Nrf 1和Nrf 2，与小Maf（sMaf）蛋白（MafF、MafG和MafK）异源二聚化，并通过CNC-sMaf结合元件（CsMBE）调节靶基因表达。我们最近开发了一种独特的拴系二聚体评估系统与小Maf三重敲除成纤维细胞相结合，这使得能够表征特定的CNC-sMaf异二聚体功能。在这项研究中，我们评估了拴系Nrf 1-MafG（T-N1 G）异二聚体的分子功能。我们发现，T-N1 G激活蛋白酶体亚基基因的表达，众所周知的Nrf 1靶基因，并特异性结合到这些基因附近的CsMBEs。还发现T-N1 G激活参与蛋白质抑制相关途径的基因，包括内质网相关降解、伴侣蛋白和泛素介导的降解途径，表明Nrf 1-MafG异二聚体调节广泛的蛋白质抑制应激反应基因。通过利用这个评估系统，我们发现，Nrf 1有可能激活典型的Nrf 2靶细胞保护基因时，强烈诱导。CCNC-sMaf转录因子的帽环转录因子Nrf 1和Nrf 2与小分子Maf（Maf）蛋白（MafF、MafG和MafK）异源二聚体化，通过CCNC-sMaf结合元件（CsMBEs）调控靶基因的表达。我们最近开发了一种独特的拴系二聚体评估系统与小Maf三重敲除成纤维细胞相结合，这使得能够表征特定的CNC-sMaf异二聚体功能。
Members of the cap'n'collar (CNC) family of transcription factors, including Nrf1 and Nrf2, heterodimerize with small Maf (sMaf) proteins (MafF, MafG, and MafK) and regulate target gene expression through CNC-sMaf-binding elements (CsMBEs). We recently developed a unique tethered dimer assessment system combined with small Maf triple-knockout fibroblasts, which enabled the characterization of specific CNC-sMaf heterodimer functions. In this study, we evaluated the molecular function of the tethered Nrf1-MafG (T-N1G) heterodimer. We found that T-N1G activates the expression of proteasome subunit genes, well-known Nrf1 target genes, and binds specifically to CsMBEs in the proximity of these genes. T-N1G was also found to activate genes involved in proteostasis-related pathways, including endoplasmic reticulum-associated degradation, chaperone, and ubiquitin-mediated degradation pathways, indicating that the Nrf1-MafG heterodimer regulates a wide range of proteostatic stress response genes. By taking advantage of this assessment system, we found that Nrf1 has the potential to activate canonical Nrf2 target cytoprotective genes when strongly induced. Our results also revealed that transposable SINE B2 repeats harbor CsMBEs with high frequency and contribute to the target gene diversity of CNC-sMaf transcription factors.Members of the cap'n'collar (CNC) family of transcription factors, including Nrf1 and Nrf2, heterodimerize with small Maf (sMaf) proteins (MafF, MafG, and MafK) and regulate target gene expression through CNC-sMaf-binding elements (CsMBEs). We recently developed a unique tethered dimer assessment system combined with small Maf triple-knockout fibroblasts, which enabled the characterization of specific CNC-sMaf heterodimer functions.