Metazoans use protein homeostasis (proteostasis) pathways to respond to adverse physiological conditions, changing environment, and aging. The nervous system regulates proteostasis in different tissues, but the mechanism is not understood. Here, we show that Caenorhabditis elegans employs biogenic amine neurotransmitters to regulate ubiquitin proteasome system (UPS) proteostasis in epithelia. Mutants for biogenic amine synthesis show decreased poly‐ubiquitination and turnover of a GFP‐based UPS substrate. Using RNA‐seq and mass spectrometry, we found that biogenic amines promote eicosanoid production from poly‐unsaturated fats (PUFAs) by regulating expression of cytochrome P450 monooxygenases. Mutants for one of these P450s share the same UPS phenotype observed in biogenic amine mutants. The production of n‐6 eicosanoids is required for UPS substrate turnover, whereas accumulation of n‐6 eicosanoids accelerates turnover. Our results suggest that sensory neurons secrete biogenic amines to modulate lipid signaling, which in turn activates stress response pathways to maintain UPS proteostasis.

中文翻译：

---

生物胺神经递质促进类二十烷酸的产生和蛋白质稳态

后生动物利用蛋白质稳态（蛋白质稳态）途径来应对不利的生理条件、环境变化和衰老。神经系统调节不同组织中的蛋白质稳态，但其机制尚不清楚。在这里，我们发现秀丽隐杆线虫利用生物胺神经递质来调节上皮细胞中的泛素蛋白酶体系统（UPS）蛋白质稳态。生物胺合成突变体显示基于 GFP 的 UPS 底物的多泛素化和周转率降低。利用 RNA 测序和质谱分析，我们发现生物胺通过调节细胞色素 P450 单加氧酶的表达来促进多不饱和脂肪 (PUFA) 产生类二十烷酸。这些 P450 之一的突变体具有与生物胺突变体中观察到的相同的 UPS 表型。n ‐6 类二十烷酸的产生是 UPS 底物周转所必需的，而n ‐6 类二十烷酸的积累会加速周转。我们的结果表明，感觉神经元分泌生物胺来调节脂质信号传导，进而激活应激反应途径以维持 UPS 蛋白质稳态。