A neuropeptide regulates cell non-autonomous protein homeostasis

The coordination of proteostasis between the brain and peripheral tissues is essential for the health and survival of all animals. In C. elegans, glia coordinate organismal proteostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPR^ER). However, the signaling molecules required remain unknown. Here, we show that glial UPR^ER activation increases levels of specific neuropeptides. We identify a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPR^ER and protect against chronic ER stress. FLP-17 signals partially through the receptor, EGL-6, to activate transcellular UPR^ER and confer stress resistance. Both XBP-1 and PERK are required for maximal FLP-17-induced UPR^ER activation, though only XBP-1 is necessary for organismal ER stress resistance. This work reveals a complex neuropeptide network initiated by glial UPR^ER activation and identifies FLP-17 as a critical mediator that coopts an existing sensory-metabolic circuit to coordinate organismal proteostasis.