ERRβ: A potent inhibitor of Nrf2 transcriptional activity

The orphan nuclear receptor, estrogen-related receptor beta (ERRβ), shares a high degree of amino acid identity with estrogen receptor alpha (ERα). Although ERRβ has been shown to be critical in embryo development, little is known about its functions and target genes. Here we report that the newly identified and most common human ortholog of ERRβ—short-form hERRβ (SFhERRβ) potently represses the transcriptional activity of NF-E2 Related Factor 2 (Nrf2) on antioxidant response element (ARE)-mediated gene expression. Nrf2 is a main regulator of the expression of phase II detoxifying enzymes and antioxidant proteins in the cellular protection against oxidative stress. SFhERRβ is the most potent inhibitor of Nrf2 transcriptional activity among the three ERR family members, ERRα, ERRβ and ERRγ. Additional analyses revealed that SFhERRβ repressed Nrf2 activity likely through physical interaction in a complex with Nrf2, not by competing for the ARE DNA-binding sites, nor by decreasing Nrf2 protein concentration. By confocal immunofluorescence microscopy, SFhERRβ alters the subcellular localization of Nrf2. Analyses using SFhERRβ deletion mutants showed that SFhERRβ interacts with Nrf2 through multiple sites. Our findings suggest that ERRβ plays a novel functional role in the Nrf2-ARE pathway. By acting as a repressor of Nrf2, ERRβ may be useful as a therapeutic target in cancer chemoprevention studies.