Poganik Jesse R, Van Hall-Beauvais Alexandra K, Long Marcus J C, Disare Michael T, Zhao Yi, Aye Yimon
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 New York, United States.
Helv Chim Acta. 2020 May;103(5). doi: 10.1002/hlca.202000041. Epub 2020 Apr 12.
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.
关键的mRNA结合蛋白HuR和AUF1据报道是哺乳动物中的应激传感器。鉴于最近有报道称这些蛋白对亲电子脂质前列腺素A2和其他氧化还原信号敏感，我们在此研究了它们对典型的氧化还原相关脂质衍生亲电试剂4-羟基壬烯醛（HNE）的传感能力。利用我们的T-REX亲电试剂递送平台，我们发现在HEK293T细胞中，只有HuR，而不是AUF1，是HNE的动力学优势传感器，并且通过特定的半胱氨酸C13进行传感。用HNE处理后，HuR缺失的细胞在细胞活力和Nrf2转录因子驱动的抗氧化反应（AR）方面表现出独特的变化，我们最近的研究表明，这在Nrf2-mRNA水平上受HuR调节。诱变研究表明，仅C13特异性传感不足以解释HuR依赖性应激反应，这进一步突出了通过HuR对Nrf2/AR进行复杂的上下文依赖性调节。
