MicroRNA-1224 Splicing CircularRNA-Filip1l in an Ago2-Dependent Manner Regulates Chronic Inflammatory Pain via Targeting Ubr5
MicroRNA-1224 Splicing CircularRNA-Filip1l in an Ago2-Dependent Manner Regulates Chronic Inflammatory Pain via Targeting Ubr5
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DOI：
10.1523/jneurosci.1631-18.2018
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发表时间：
2019-03-13
影响因子：
5.3
通讯作者：
Cao, Jun-Li
中科院分区：
文献类型：
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作者：
Pan, Zhiqiang;Li, Guo-Fang;Cao, Jun-Li
痛觉通路中基因转录和翻译的功能障碍在慢性疼痛的发生和维持中起着关键作用。环状rna （circRNAs）正在成为基因表达调控的新参与者，但环状rna是否以及如何参与慢性疼痛仍然难以捉摸。我们在这里发现，完全弗氏佐剂诱导的慢性炎症性疼痛显著增加了小鼠脊髓神经元中circRNA-Filipi1l（丝蛋白A相互作用蛋白1样）的表达。阻断这种增加减弱了完全的弗氏佐剂诱导的伤害性行为，幼稚小鼠中脊髓环状rna - filipi1l的过度表达模仿了伤害性行为，这可以通过降低热和机械伤害性阈值来证明。此外，我们发现miRNA-1224通过Argonaute-2 （Ago2）依赖性的方式结合和剪接circRNA-Filipi1l前体（pre-circRNA-Filipi1l），负调控成熟circrna - filiplil的表达。慢性炎症疼痛状态下，脊髓circRNA-Filipi1l表达升高是由于m - iRNA-1224表达降低所致。miRNA-1224敲低或Ago2过表达可诱导幼稚小鼠产生伤害性行为，而脊髓环状rna - filipi1l敲低可阻止这种行为。最后，我们证实了一种泛素蛋白连接酶E3组分n-识别蛋白5 (Ubr5)，作为circRNA-Filipi1l的靶标，在脊髓circRNA-Filipi1l对伤害性的调节中起着关键作用。这些数据表明，miRNA-1224介导和ago2依赖的脊柱circRNA- filipi1l表达调节通过靶向Ubr5来调节伤害感受，揭示了miRNA和circRNA在慢性炎症疼痛中相互作用的一种新的表观遗传机制。
Dysfunctions of gene transcription and translation in the nociceptive pathways play the critical role in development and maintenance of chronic pain. Circular RNAs (circRNAs) are emerging as new players in regulation of gene expression, but whether and how circRNAs are involved in chronic pain remain elusive. We showed here that complete Freund's adjuvant-induced chronic inflammation pain significantly increased circRNA-Filipi1l (filamin A interacting protein 1-like) expression in spinal neurons of mice. Blockage of this increase attenuated complete Freund's adjuvant-induced nociceptive behaviors, and overexpression of spinal circRNA-Filipi1l in naive mice mimicked the nociceptive behaviors as evidenced by decreased thermal and mechanical nociceptive threshold. Furthermore, we found that mature circ RNA-Filipllexpression was negatively regulated by miRNA-1224 via binding and splicing of precursor of circRNA-Filipi1l (pre-circRNA-Filipi1l) in the Argonaute-2 (Ago2)-dependent manner. Increase of spinal circRNA-Filipi1l expression resulted from the decrease of m iRNA-1224 expression under chronic inflammation pain state. miRNA-1224 knockdown or Ago2 overexpression induced nociceptive behaviors in naive mice, which was prevented by the knockdown of spinal circRNA-Filipi1l. Finally, we demonstrated that a ubiquitin protein ligase E3 component n-recognin 5 (Ubr5), validated as a target of circRNA-Filipi1l, plays a pivotal role in regulation of nociception by spinal circRNA-Filipi1l. These data suggest that miRNA-1224-mediated and Ago2-dependent modulation of spinal circRNA-Filipi1l expression regulates nociception via targeting Ubr5, revealing a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.