Post-transcriptional regulation of Nrf2-mRNA by the mRNA-binding proteins HuR and AUF1

Abstract The Nrf2-driven antioxidant response (AR) is a target of covalent drugs and bioactive native electrophiles. However, much of our understanding of AR has centered on protein-level regulation of Nrf2. Here we report a post-transcriptional modality to directly regulate Nrf2-mRNA. Our initial studies focused on the effects of the key mRNA-binding protein (mRBP) HuR on global transcriptomic changes incurred upon oxidant or electrophile stimulation. These data led us to discover a novel role of HuR in regulating Nrf2/AR, and in the process we further identified the related mRBP AUF1 as an additional novel Nrf2/AR regulator. Both mRBPs regulate AR by direct interaction with the Nrf2 transcript. Our data showed that HuR enhances Nrf2-mRNA maturation and promotes its nuclear export; whereas AUF1 stabilizes Nrf2-mRNA. Both mRBPs target the 3′–UTR of Nrf2-mRNA. Using an AR-reporter zebrafish strain, we document that this post-transcriptional control of AR is conserved at the whole-vertebrate level.