In C. elegans, expression of the UPR^ER transcription factor xbp-1s in neurons cell non-autonomously activates the UPR^ER in the intestine, leading to enhanced proteostasis and lifespan. To better understand this signaling pathway, we isolated neurons from animals expressing neuronal xbp-1s for transcriptomic analysis, revealing a striking remodeling of transcripts involved in neuronal signaling. We then identified signaling molecules required for cell non-autonomous intestinal UPR^ER activation, including the biogenic amine tyramine. Expression of xbp-1s in just two pairs of neurons that synthesize tyramine, the RIM and RIC interneurons, induced intestinal UPR^ER activation and extended longevity, and exposure to stress led to splicing and activation of xbp-1 in these neurons. In addition, we found that neuronal xbp-1s modulates feeding behavior and reproduction, dependent upon tyramine synthesis. XBP-1s therefore remodels neuronal signaling to coordinately modulate intestinal physiology and stress-responsive behavior, functioning as a global regulator of organismal responses to stress.

在秀丽隐杆线虫中，神经元细胞中 UPR ^ER转录因子xbp-1s的表达会非自主地激活肠道中的 UPR ^ER ，从而增强蛋白质稳态并延长寿命。为了更好地理解这一信号通路，我们从表达神经元xbp-1 的动物中分离出神经元进行转录组分析，揭示了参与神经元信号传导的转录物的惊人重塑。然后，我们鉴定了细胞非自主肠道 UPR ^ER激活所需的信号分子，包括生物胺酪胺。 xbp-1在合成酪胺的两对神经元（RIM 和 RIC 中间神经元）中表达，诱导肠道 UPR ^ER激活并延长寿命，而暴露于压力会导致这些神经元中xbp-1的剪接和激活。此外，我们发现神经元xbp-1s依赖于酪胺合成来调节摄食行为和繁殖。因此，XBP-1 重塑神经元信号传导以协调调节肠道生理和应激反应行为，充当机体对应激反应的全局调节器。