The Cytidine N-Acetyltransferase NAT10 Participates in Peripheral Nerve Injury-Induced Neuropathic Pain by Stabilizing SYT9 Expression in Primary Sensory Neurons
- Ming Zhang1,*,
- Kehui Yang1,*,
- Qi-Hui Wang1,*,
- Ling Xie2,
- Qiaoqiao Liu1,
- Runa Wei1,
- Yang Tao1,
- Hong-Li Zheng3,
- Ninghua Lin4,
- Hengjun Xu1,
- Li Yang1,
- Hongjun Wang1,
- Tingruo Zhang1,
- Zhouya Xue5,
- Jun-Li Cao1, and
- Zhiqiang Pan1
- 1Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou 221004, China
- 2Department of Anesthesiology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- 3Department of Pain, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
- 4Department of Anesthesiology, Yantai affiliated Hospital of Binzhou Medical University, Yantai 264000, China
- 5Department of Anesthesiology, Yancheng affiliated Hospital of Xuzhou Medical University, Yancheng 224008, China
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Author contributions: M.Z., Q.-H.W., L.Y., H.W., J.-L.C., and Z.P. designed research; M.Z., K.Y., L.X., Q.L., R.W., Y.T., H.-L.Z., N.L., H.X., and T.Z. performed research; M.Z., Q.-H.W., L.Y., H.W., Z.X., and Z.P. analyzed data; M.Z. wrote the first draft of the paper; M.Z. and Z.P. edited the paper; M.Z. and Z.P. wrote the paper.
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↵*M.Z., K.Y., and Q.-H.W. contributed equally to this work.
Abstract
RNA N4-acetylcytidine (ac4C) modification is increasingly recognized as an important layer of gene regulation; however, the involvement of ac4C in pain regulation has not been studied. Here, we report that N-acetyltransferase 10 protein (NAT10; the only known ac4C “writer”) contributes to the induction and development of neuropathic pain in an ac4C-dependent manner. Peripheral nerve injury increases the levels of NAT10 expression and overall ac4C in injured dorsal root ganglia (DRGs). This upregulation is triggered by the activation of upstream transcription factor 1 (USF1), a transcription factor that binds to the Nat10 promoter. Knock-down or genetic deletion of NAT10 in the DRG abolishes the gain of ac4C sites in Syt9 mRNA and the augmentation of SYT9 protein, resulting in a marked antinociceptive effect in nerve-injured male mice. Conversely, mimicking NAT10 upregulation in the absence of injury evokes the elevation of Syt9 ac4C and SYT9 protein and induces the genesis of neuropathic-pain-like behaviors. These findings demonstrate that USF1-governed NAT10 regulates neuropathic pain by targeting Syt9 ac4C in peripheral nociceptive sensory neurons. Our findings establish NAT10 as a critical endogenous initiator of nociceptive behavior and a promising new target for treating neuropathic pain.
SIGNIFICANCE STATEMENT The cytidine N4-acetylcytidine (ac4C), a new epigenetic RNA modification, is crucial for the translation and stability of mRNA, but its role for chronic pain remains unclear. Here, we demonstrate that N-acetyltransferase 10 (NAT10) acts as ac4C N-acetyltransferase and plays an important role in the development and maintenance of neuropathic pain. NAT10 was upregulated via the activation of the transcription factor upstream transcription factor 1 (USF1) in the injured dorsal root ganglion (DRG) after peripheral nerve injury. Since pharmacological or genetic deleting NAT10 in the DRG attenuated the nerve injury-induced nociceptive hypersensitivities partially through suppressing Syt9 mRNA ac4C and stabilizing SYT9 protein level, NAT10 may serve as an effective and novel therapeutic target for neuropathic pain.
- Received December 20, 2022.
- Revision received February 23, 2023.
- Accepted March 1, 2023.
- Copyright © 2023 the authors
