Abstract：
Post-transcriptional regulation of cytokine/chemokine mRNA turnover is critical for immune processes and contributes to the mammalian cellular response to diverse inflammatory stimuli. The ubiquitous RNA-binding protein human antigen R (HuR) is an integral regulator of inflammation-associated mRNA fate. HuR function is regulated by various post-translational modifications that alter its subcellular localization and ability to stabilize target mRNAs. Both poly (ADP-ribose) polymerase 1 (PARP1) and p38 mitogen-activated protein kinases (MAPKs) have been reported to regulate the biological function of HuR, but their specific regulatory and crosstalk mechanisms remain unclear. In this study, we show that PARP1 acts via p38 to synergistically promote cytoplasmic accumulation of HuR and stabilization of inflammation-associated mRNAs in cells under inflammatory conditions. Specifically, p38 binds to auto-poly ADP-ribosylated (PARylated) PARP1 resulting in the covalent PARylation of p38 by PARP1, thereby promoting the retention and activity of p38 in the nucleus. In addition, PARylation of HuR facilitates the phosphorylation of HuR at the serine 197 site mediated by p38, which then increases the translocation of HuR to the cytoplasm, ultimately stabilizing the inflammation-associated mRNA expression at the post-transcriptional level.
摘要：
细胞因子/趋化因子mRNA转换的转录后调节对于免疫过程至关重要，并有助于哺乳动物细胞对多种炎症刺激的反应。普遍存在的RNA结合蛋白人抗原R（HuR）是炎症相关mRNA命运的完整调节因子。HuR功能受多种翻译后修饰调节,所述翻译后修饰改变其亚细胞定位和稳定靶mRNA的能力。已经报道了聚（ADP-核糖）聚合酶1（PARP1）和p38丝裂原活化蛋白激酶（MAPK）调节HuR的生物学功能，但其具体的调控和串扰机制尚不清楚。在这项研究中,我们显示PARP1通过p38协同促进HuR的细胞质积累和炎症条件下细胞中炎症相关mRNA的稳定。具体来说,p38与自身聚ADP-核糖基化(PARylated)PARP1结合,导致P38被PARP1共价PARylation,从而促进p38在核中的保留和活性。此外,HuR的PARylation促进了由p38介导的在丝氨酸197位点处的HuR的磷酸化,从而增加了HuR向细胞质的易位,最终在转录后水平稳定炎症相关的mRNA表达。
