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The mRNA-Binding Protein HuR Is a Kinetically-Privileged Electrophile Sensor |
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| Authors: | Jesse R. Poganik Alexandra K. Van Hall-Beauvais Marcus J. C. Long Michael T. Disare Yi Zhao Yimon Aye |
| Affiliation: | 1. Institute of Chemical Sciences & Engineering (ISIC), Swiss Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne Department of Chemistry & Chemical Biology, Cornell University, Ithaca, New York, 14853 United States These authors contributed equally.;2. Institute of Chemical Sciences & Engineering (ISIC), Swiss Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne These authors contributed equally.;3. Department of Chemistry & Chemical Biology, Cornell University, Ithaca, New York, 14853 United States;4. Institute of Chemical Sciences & Engineering (ISIC), Swiss Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne |
| Abstract: | The key mRNA-binding proteins HuR and AUF1 are reported stress sensors in mammals. Intrigued by recent reports of sensitivity of these proteins to the electrophilic lipid prostaglandin A2 and other redox signals, we here examined their sensing abilities to a prototypical redox-linked lipid-derived electrophile, 4-hydroxynonenal (HNE). Leveraging our T-REX electrophile delivery platform, we found that only HuR, and not AUF1, is a kinetically-privileged sensor of HNE in HEK293T cells, and sensing functions through a specific cysteine, C13. Cells depleted of HuR, upon treatment with HNE, manifest unique alterations in cell viability and Nrf2-transcription-factor-driven antioxidant response (AR), which our recent work shows is regulated by HuR at the Nrf2-mRNA level. Mutagenesis studies showed that C13-specific sensing alone is not sufficient to explain HuR-dependent stress responsivities, further highlighting a complex context-dependent layer of Nrf2/AR regulation through HuR. |
| Keywords: | mRNA-binding protein mRNA 4-hydroxynonenal electrophile sensor sensors antioxidant response HuR AUF1 Nrf2 |