mRNA translation is integral to pain, yet the key regulatory factors and their target mRNAs are unclear. Here, we uncover a mechanism that bridges noxious insults to multiple phases of translational control in murine sensory neurons. We find that a painful cue triggers repression of peptide chain elongation through activation of elongation factor 2 kinase (eEF2K). Attenuated elongation is sensed by a ribosome-coupled mechanism that triggers the integrated stress response (ISR). Both eEF2K and the ISR are required for pain-associated behaviors in vivo. This pathway simultaneously induces biosynthesis of brain-derived neurotrophic factor (BDNF). Selective blockade of Bdnf translation has analgesic effects in vivo. Our data suggest that precise spatiotemporal regulation of Bdnf translation is critical for appropriate behavioral responses to painful stimuli. Overall, our results demonstrate that eEF2K resides at the nexus of an intricate regulatory network that links painful cues to multiple layers of translational control.

中文翻译：

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eEF2K 通过 BDNF 的翻译控制调节疼痛


mRNA 翻译是疼痛不可或缺的一部分，但关键调节因子及其靶标 mRNA 尚不清楚。在这里，我们发现了一种将有害损伤与小鼠感觉神经元翻译控制的多个阶段联系起来的机制。我们发现，痛苦的提示通过激活延伸因子 2 激酶 （eEF2K） 触发肽链伸长的抑制。衰减伸长由触发综合应力反应 （ISR） 的核糖体偶联机制感知。eEF2K 和 ISR 都是体内疼痛相关行为 所必需的。该途径同时诱导脑源性神经营养因子 （BDNF） 的生物合成。选择性阻断 Bdnf 翻译在 体内具有镇痛作用。我们的数据表明，Bdnf 翻译的精确时空调节对于对疼痛刺激的适当行为反应至关重要。总体而言，我们的结果表明 eEF2K 位于一个错综复杂的监管网络的纽带，该网络将痛苦的线索与多层翻译控制联系起来。