Huang Yue, Ma Gan, Xie Shan, Wei Runa, Liu Ya, Zeng Ying, Zhao Yaxuan, Wang Qihui, Yang Li, Huang Huiying, Hao Lingyun, Zhao Xiaotian, Wang Hongjun, Shen Wen, Wong Stanley Sau Ching, Cao Jun-Li, Tao Yuan-Xiang, Pan Zhi-Qiang
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, XuzhouMedical University, Xuzhou, Jiangsu, China.
Nat Commun. 2025 Aug 5;16(1):7225. doi: 10.1038/s41467-025-62565-5.
Nerve injury-induced changes in pain-associated genes contribute to genesis of neuropathic pain and comorbid anxiety. Phosphorylated CTD interacting factor-1 (PCIF1)-triggered N6, 2'-O-dimethyladenosine (mAm) mRNA modification represents an additional layer of gene regulation. However, the role of PCIF1 in these disorders is elusive. Here, we report PCIF1 is increased in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex in mouse with neuropathic pain and anxiety, but not inflammatory pain or anxiety alone. Serpine-1 mRNA-binding protein-1 (SERBP1) is identified as a PCIF1 cofactor, their complex mediates mAm deposition onto mRNA. Blocking SERBP1-PCIF1 upregulation in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex abolishes mAm gain on maf1 homolog, negative regulator of RNA polymerase III (Maf1), elevates MAF1 protein, and mitigates neuropathic pain and anxiety. Conversely, mimicking this increase adds mAm onto Maf1, reduces MAF1, and induces comorbidity symptoms. These findings highlight the significance of mAm in neuropathic pain-anxiety comorbidity and identify SERBP1-PCIF1 in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex as a potential therapeutic target.
神经损伤诱导的疼痛相关基因变化促成神经性疼痛和共病焦虑的发生。磷酸化CTD相互作用因子-1（PCIF1）触发的N6,2'-O-二甲基腺苷（mAm）mRNA修饰代表了基因调控的另一个层面。然而，PCIF1在这些疾病中的作用尚不清楚。在此，我们报告在患有神经性疼痛和焦虑的小鼠中，初级体感皮层后肢区域的谷氨酸能神经元中PCIF1增加，但在单独患有炎性疼痛或焦虑的小鼠中则没有增加。丝氨酸蛋白酶抑制剂-1 mRNA结合蛋白-1（SERBP1）被鉴定为PCIF1的辅因子，它们的复合物介导mAm沉积到mRNA上。阻断初级体感皮层后肢区域谷氨酸能神经元中SERBP1-PCIF1的上调可消除RNA聚合酶III负调节因子maf1同源物（Maf1）上的mAm增加，提高MAF1蛋白水平，并减轻神经性疼痛和焦虑。相反，模拟这种增加会在Maf1上添加mAm，降低MAF1，并诱发共病症状。这些发现突出了mAm在神经性疼痛-焦虑共病中的重要性，并确定初级体感皮层后肢区域谷氨酸能神经元中的SERBP1-PCIF1为潜在的治疗靶点。
