The mRNA-binding protein HuR is a kinetically-privileged electrophile sensor

The key mRNA-binding proteins HuR and AUF1 are reported stress sensors in mammals. Intrigued by recent reports ofsensitivity of these proteins to the electrophilic lipid prostaglandin A2 and other redox signals, we here examined their sensingabilities to a prototypical redox-linked lipid-derived electrophile, 4-hydroxynonenal (HNE). Leveraging our T-REX electrophiledelivery platform, we found that only HuR, and not AUF1, is a kinetically-privileged sensor of HNE in HEK293T cells, andsensing functions through a specific cysteine, C13. Cells depleted of HuR, upon treatment with HNE, manifest uniquealterations in cell viability and Nrf2-transcription-factor-driven antioxidant response (AR), which our recent work shows isregulated by HuR at the Nrf2-mRNA level. Mutagenesis studies showed that C13-specific sensing alone is not sufficient toexplain HuR-dependent stress responsivities, further highlighting a complex context-dependent layer of Nrf2/AR regulationthrough HuR.