The Key Laboratory of Molecular Epigenetics of the Ministry of Education, School of Life Science, Northeast Normal University, Changchun, 130024, Jilin, China.
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Cell Mol Life Sci. 2021 Feb;78(4):1817-1835. doi: 10.1007/s00018-020-03618-4. Epub 2020 Aug 13.
Poly(ADP-ribosyl)ation (PARylation) is an important post-translational modification mainly catalyzed by poly-ADP-ribose polymerase 1 (PARP1). In addition to having important roles in DNA damage detection and repair, it functions in gene expression regulation, especially at the posttranscriptional level. Embryonic lethal abnormal vision-like 1/human antigen R (ELAVL/HuR), a canonical 3' untranslated region AU-rich element-binding protein, is a crucial mRNA-stabilizing protein that protects target mRNAs from RNA-destabilizing protein- or microRNA-induced silencing complex (miRISC)-mediated degradation. Additionally, in some cases, HuR itself either promotes or suppresses translation. Here, we demonstrated that in response to inflammatory stimuli, the PARylation of HuR, mostly at the conserved D226 site, by PARP1 increased the formation of the HuR oligomer/multimer, and HuR oligomerization promoted the disassociation of miRISC and stabilized the pro-inflammatory gene mRNAs. The prevention of PARP1 activation or HuR oligomerization attenuated lipopolysaccharide-induced inflammatory gene expression and the airway recruitment of neutrophils in mouse lungs. The present study verified a novel mechanism of PARP1 and HuR PARylation in the RNA stability regulation, increasing our understanding of how PARP1 regulates gene expression.
聚（ADP-核糖）化（PARylation）是一种重要的翻译后修饰，主要由聚 ADP-核糖聚合酶 1（PARP1）催化。除了在 DNA 损伤检测和修复中发挥重要作用外，它还在基因表达调控中发挥作用，特别是在转录后水平。胚胎致死异常视觉样 1/人抗原 R（ELAVL/HuR）是一种典型的 3'非翻译区 AU 富集元件结合蛋白，是一种至关重要的 mRNA 稳定蛋白，可防止靶 mRNA 被 RNA 不稳定蛋白或 microRNA 诱导的沉默复合物（miRISC）介导的降解。此外，在某些情况下，HuR 本身促进或抑制翻译。在这里，我们证明了在炎症刺激下，PARP1 对 HuR 的 PARylation（主要在保守的 D226 位点）增加了 HuR 寡聚体/多聚体的形成，并且 HuR 寡聚化促进了 miRISC 的解离并稳定了促炎基因 mRNA。预防 PARP1 激活或 HuR 寡聚化可减弱脂多糖诱导的炎症基因表达和小鼠肺部中性粒细胞的气道募集。本研究验证了 PARP1 和 HuR PARylation 在 RNA 稳定性调节中的一种新机制，增加了我们对 PARP1 如何调节基因表达的理解。
