Inhibition of Nonsense-Mediated Decay Induces Nociceptive Sensitization through Activation of the Integrated Stress Response
Inhibition of Nonsense-Mediated Decay Induces Nociceptive Sensitization through Activation of the Integrated Stress Response
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DOI：
10.1523/jneurosci.1604-22.2023
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发表时间：
2023-04-19
影响因子：
5.3
通讯作者：
Campbell, Zachary T.
中科院分区：
文献类型：
--
作者：
de la Pena, June Bryan;Chase, Rebecca;Campbell, Zachary T.
RNA的稳定性受到严格控制。在这里，我们试图确定一个基本的转录后调节机制是否在疼痛中起作用。无义介导的衰变（NMD）保护含有过早终止密码子的mrna的翻译并控制其稳定性；10%的典型蛋白质编码mrna。它取决于保守的激酶SMG1的活性。SMG1及其靶点UPF1均在小鼠DRG感觉神经元中表达。SMG1蛋白存在于DRG和坐骨神经中。通过高通量测序，我们检测了抑制SMG1后mRNA丰度的变化。我们在感觉神经元中确认了包括ATF4在内的多个NMD稳定性靶点。ATF4在综合应力响应（integrated stress response， ISR）过程中优先翻译。这让我们不禁要问，NMD的暂停是否会诱发ISR。抑制NMD增加了eIF2-a磷酸化，降低了eIF2-a磷酸化的磷酸酶组成抑制因子的丰度。最后，我们研究了SMG1抑制对疼痛相关行为的影响。外周抑制SMG1导致男性和女性机械性超敏反应持续数天，并引发阈下剂量的PGE2。ISR的小分子抑制剂完全挽救了启动。总的来说，我们的结果表明NMD的暂停通过刺激ISR来促进疼痛。
RNA stability is meticulously controlled. Here, we sought to determine whether an essential post-transcriptional regulatory mechanism plays a role in pain. Nonsense-mediated decay (NMD) safeguards against translation of mRNAs that harbor premature termination codons and controls the stability of ;10% of typical protein-coding mRNAs. It hinges on the activity of the conserved kinase SMG1. Both SMG1 and its target, UPF1, are expressed in murine DRG sensory neurons. SMG1 protein is present in both the DRG and sciatic nerve. Using high-throughput sequencing, we examined changes in mRNA abundance following inhibition of SMG1. We confirmed multiple NMD stability targets in sensory neurons, including ATF4. ATF4 is preferentially translated during the integrated stress response (ISR). This led us to ask whether suspension of NMD induces the ISR. Inhibition of NMD increased eIF2-a phosphorylation and reduced the abundance of the eIF2-a phosphatase constitutive repressor of eIF2-a phosphorylation. Finally, we examined the effects of SMG1 inhibition on pain-associated behaviors. Peripheral inhibition of SMG1 results in mechanical hypersensitivity in males and females that persists for several days and priming to a subthreshold dose of PGE2. Priming was fully rescued by a small-molecule inhibitor of the ISR. Collectively, our results indicate that suspension of NMD promotes pain through stimulation of the ISR.