<br>Ac4C 增强 Vegfa mRNA 的翻译效率并介导神经性疼痛中脊髓背角的中枢敏化,Advanced Science

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Ac4C 增强 Vegfa mRNA 的翻译效率并介导神经性疼痛中脊髓背角的中枢敏化
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-25 , DOI: 10.1002/advs.202303113
Ting Xu ₁ , Jing Wang _{1,

2} , Yan Wu ₃ , Jia-Yan Wu ₁ , Wei-Cheng Lu ₄ , Meng Liu ₅ , Su-Bo Zhang ₄ , Dan Xie ₄ , Wen-Jun Xin ₁ , Jing-Dun Xie ₄

Affiliation

N4-乙酰胞苷 (ac4C) 是一种高度保守的转录后机制，广泛存在于 RNA 修饰中，在各种细胞过程和功能中发挥着多种作用。然而，ac4C 修饰介导神经性疼痛的分子机制仍不清楚。在这里，我们发现增强的 ac4C 修饰促进了 Vegfa mRNA 中多核糖体的募集，并增强了 SNI 后的翻译效率。神经损伤增加了背角神经元中NAT10的表达以及NAT10与Vegfa mRNA之间的相互作用，NAT10功能的获得和丧失进一步证实NAT10参与了Vegfa mRNA中的ac4C修饰和疼痛行为。此外，ac4C 介导的 VEGFA 上调有助于 SNI 或 AAV-hSyn-NAT10 诱导的中枢敏感性和神经性疼痛。最后，SNI 促进 Vegfa mRNA 中 HNRNPK 的结合，随后招募 NAT10。 HNRNPK 和 NAT10 之间相互作用的增强有助于 Vegfa mRNA 的 ac4C 修饰和神经性疼痛。这些发现表明，HNRNPK 和 Vegfa mRNA 之间增强的相互作用通过招募 NAT10 上调 ac4C 水平，并有助于 SNI 后的中枢敏感性和神经性疼痛。阻断这种级联反应可能是神经性疼痛患者的一种新的治疗方法。

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Ac4C Enhances the Translation Efficiency of Vegfa mRNA and Mediates Central Sensitization in Spinal Dorsal Horn in Neuropathic Pain

N4-Acetylcytidine (ac4C), a highly conserved post-transcriptional machinery with extensive existence for RNA modification, plays versatile roles in various cellular processes and functions. However, the molecular mechanism by which ac4C modification mediates neuropathic pain remains elusive. Here, it is found that the enhanced ac4C modification promotes the recruitment of polysome in Vegfa mRNA and strengthens the translation efficiency following SNI. Nerve injury increases the expression of NAT10 and the interaction between NAT10 and Vegfa mRNA in the dorsal horn neurons, and the gain and loss of NAT10 function further confirm that NAT10 is involved in the ac4C modification in Vegfa mRNA and pain behavior. Moreover, the ac4C-mediated VEGFA upregulation contributes to the central sensitivity and neuropathic pain induced by SNI or AAV-hSyn-NAT10. Finally, SNI promotes the binding of HNRNPK in Vegfa mRNA and subsequently recruits the NAT10. The enhanced interaction between HNRNPK and NAT10 contributes to the ac4C modification of Vegfa mRNA and neuropathic pain. These findings suggest that the enhanced interaction between HNRNPK and Vegfa mRNA upregulates the ac4C level by recruiting NAT10 and contributes to the central sensitivity and neuropathic pain following SNI. Blocking this cascade may be a novel therapeutic approach in patients with neuropathic pain.

更新日期：2023-10-25

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