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Poly(ADP-ribosyl)ation enhances HuR oligomerization and contributes to pro-inflammatory gene mRNA stabilization.
Cellular and Molecular Life Sciences ( IF 8 ) Pub Date : 2020-08-13 , DOI: 10.1007/s00018-020-03618-4
Yueshuang Ke 1 , Xueping Lv 1 , Xingyue Fu 1 , Jing Zhang 1 , Ameer Ali Bohio 1 , Xianlu Zeng 1 , Wenjing Hao 2 , Ruoxi Wang 3 , Istvan Boldogh 4 , Xueqing Ba 1
Affiliation  

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.



中文翻译:

聚(ADP-核糖基)化增强HuR寡聚并有助于促炎基因mRNA稳定化。

聚(ADP-核糖基)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,它还可以在基因表达调节中起作用,尤其是在转录后水平上。胚胎致死性异常视觉样1 /人类抗原R(ELAVL / HuR),一种典型的3'非翻译区富含AU的元素结合蛋白,是一种重要的mRNA稳定蛋白,可保护靶mRNA免受RNA不稳定的蛋白或microRNA的侵害-诱导的沉默复合物(miRISC)介导的降解。此外,在某些情况下,HuR本身会促进或抑制翻译。在这里,我们证明了针对炎症刺激,HuR的PARylation(主要在保守的D226位点)PARP1的作用增加了HuR寡聚体/多聚体的形成,HuR寡聚化促进了miRISC的解离并稳定了促炎基因的mRNA。预防PARP1激活或HuR寡聚化可减轻脂多糖诱导的炎症基因表达和小鼠肺中性粒细胞的气道募集。本研究证实了RNA稳定调节中PARP1和HuR PARylation的新机制,增加了我们对PARP1如何调节基因表达的了解。

更新日期:2020-08-14
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