DHX9/DNA-tandem repeat-dependent downregulation of ciRNA-Fmn1 in the dorsal horn is required for neuropathic pain
DHX9/DNA-tandem repeat-dependent downregulation of ciRNA-Fmn1 in the dorsal horn is required for neuropathic pain
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DOI：
10.1038/s41401-023-01082-x
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发表时间：
2023-04
影响因子：
8.2
通讯作者：
Xiaodan Liu;Tong Jin;Yang Tao;Ming Zhang;Hong-Li Zheng;Qiaoqiao Liu;Kehui Yang;Runa Wei
中科院分区：
文献类型：
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作者：
Xiaodan Liu;Tong Jin;Yang Tao;Ming Zhang;Hong-Li Zheng;Qiaoqiao Liu;Kehui Yang;Runa Wei
环状RNA（ciRNA）正在成为基因表达调控的新参与者。然而，人们对ciRNA如何参与神经性疼痛知之甚少。在这里，我们确定了神经组织特异性的ciRNA-Fmn 1，并报告说，改变ciRNA-Fmn 1在脊髓背角神经元的表达在神经损伤后的神经病理性疼痛中发挥关键作用。ciRNA-Fmn 1在周围神经损伤后的同侧背角神经元中显著下调，至少部分是因为DNA解旋酶9（DHX 9）的减少，该酶通过与DNA串联重复序列结合来调节ciRNA-Fmn 1的产生。阻断ciRNA-Fmn 1下调逆转了神经损伤诱导的ciRNA-Fmn 1与泛素连接酶UBR 5结合和白蛋白（ALB）泛素化水平的降低，从而消除了神经损伤诱导的背角ALB表达增加，并减弱了相关的疼痛超敏反应。相反，在未处理小鼠中模拟下调ciRNA-Fmn 1减少了UBR 5控制的ALB泛素化，导致未处理小鼠背角中ALB表达增加并诱导神经病理性疼痛样行为。因此，DHX 9与DNA串联重复序列结合的变化引起的ciRNA-Fmn 1下调通过负性调节背角中UBR 5控制的ALB表达而促成神经性疼痛的发生。
Circular RNAs (ciRNAs) are emerging as new players in the regulation of gene expression. However, how ciRNAs are involved in neuropathic pain is poorly understood. Here, we identify the nervous-tissue-specificciRNA-Fmn1and report that changes inciRNA-Fmn1expression in spinal cord dorsal horn neurons play a key role in neuropathic pain after nerve injury.ciRNA-Fmn1was significantly downregulated in ipsilateral dorsal horn neurons after peripheral nerve injury, at least in part because of a decrease in DNA helicase 9 (DHX9), which regulates production ofciRNA-Fmn1by binding to DNA-tandem repeats. BlockingciRNA-Fmn1downregulation reversed nerve-injury-induced reductions in both the binding ofciRNA-Fmn1to the ubiquitin ligase UBR5 and the level of ubiquitination of albumin (ALB), thereby abrogating the nerve-injury-induced increase of ALB expression in the dorsal horn and attenuating the associated pain hypersensitivities. Conversely, mimicking downregulation ofciRNA-Fmn1in naïve mice reduced the UBR5-controlled ubiquitination of ALB, leading to increased expression of ALB in the dorsal horn and induction of neuropathic-pain-like behaviors in naïve mice. Thus,ciRNA-Fmn1downregulation caused by changes in binding of DHX9 to DNA-tandem repeats contributes to the genesis of neuropathic pain by negatively modulating UBR5-controlled ALB expression in the dorsal horn.