Tyramine Acts Downstream of Neuronal XBP-1s to Coordinate Inter-tissue UPRER Activation and Behavior in C. elegans

In C. elegans, expression of the UPRER transcription factor xbp-1s in neurons cell non-autonomously activates the UPRER 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 UPRER 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 UPRER 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. [Display omitted] •XBP-1s drives a distinct transcriptional program in C. elegans neurons•Neuronal XBP-1s requires tyramine synthesis to induce intestinal UPR activation•XBP-1s expression in RIM and RIC neurons drives cell non-autonomous UPR activation•Neuronal XBP-1s changes behavior and reproduction, dependent on tyramine synthesis Neuronal XBP-1s expression drives intestinal UPRER activation in C. elegans. Özbey et al. define the transcriptional targets of neuronal XBP-1s and find that tyramine and the RIM/RIC interneurons are required for distal UPR activation. Neuronal XBP-1s also modulates behavior and reproduction in a tyramine-dependent manner, globally coordinating organismal responses to stress.