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

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.