A FMRF-amide peptide that regulates cell non-autonomous protein homeostasis in C. elegans

The coordination of protein homeostasis from the brain to periphery is essential for the health and survival of all animals. In C. elegans , glia serve a central role in coordinating organismal protein homeostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPR ^ER ). However, the full extent of the cell non-autonomous response and the identity of the signaling molecules required remained unknown. Here, we show that glial UPR ^ER activation induces robust transcriptomic changes in specific tissue types across the animal, particularly in pathways related to neuropeptide signaling. We performed neuropeptidomics and loss and gain-of-function genetic screens and identified a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPR ^ER . FLP-17 is sufficient to protect against chronic ER stress and age-dependent protein aggregation. We determined that FLP-17 acts through the receptor, EGL-6, to activate cell non-autonomous UPR ^ER . This work reveals a complex peptidergic signaling network initiated by glial activation of the UPR ^ER to regulate organismal protein homeostasis.