Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Epigenetics Programme, The Babraham Institute, Babraham CB22 3AT, UK.
Dev Cell. 2020 Dec 21;55(6):754-770.e6. doi: 10.1016/j.devcel.2020.10.024. Epub 2020 Nov 23.
In C. elegans, expression of the UPR transcription factor xbp-1s in neurons cell non-autonomously activates the UPR 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 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 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，UPR 转录因子 xbp-1s 在神经元中的表达非自主地激活了肠道中的 UPR，导致蛋白质稳态和寿命的增强。为了更好地理解这个信号通路，我们从表达神经元 xbp-1s 的动物中分离出神经元进行转录组分析，揭示了涉及神经元信号的转录本的惊人重塑。然后，我们确定了细胞非自主肠道 UPR 激活所需的信号分子，包括生物胺酪胺。仅在合成酪胺的两对神经元（RIM 和 RIC 中间神经元）中表达 xbp-1s，就会诱导肠道 UPR 激活和延长寿命，而应激暴露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 调节摄食行为和生殖，这取决于酪胺的合成。因此，XBP-1s 重塑神经元信号以协调调节肠道生理学和应激反应行为，作为生物体对应激反应的全局调节剂。
