FLP-17’s role in stress resistance aligns with its established functions. FLP-17 belongs to an evolutionarily conserved class, FMRF-amide/RF-amide neuropeptides, that plays important roles in energy balance and reproduction across phyla.^34,35 In C. elegans, FLP-17 is secreted from a pair of sensory neurons (BAG) in response to low oxygen and high carbon dioxide, which can be caused by unfavorable food conditions or pathogens.^36,37 FLP-17 then acts through specific neurons to inhibit egg laying and initiate an aversion behavior until the animal has reached more favorable conditions.^30,36 Interestingly, unfavorable food conditions and pathogens also threaten organismal protein homeostasis.^33,38 Therefore, we speculate that FLP-17 evolved to simultaneously protect the animal from proteotoxic stress while facilitating a behavioral program to help the animal navigate to more favorable conditions.

To coordinate adaptive behavioral and metabolic responses, FLP-17 primarily signals through the GPCR EGL-6 in specific neurons.^30,31 Therefore, we tested whether EGL-6 also mediates FLP-17’s role in UPR^ER activation and found that FLP-17-induced activation of the UPR^ER and ER stress resistance is partially dependent on EGL-6. Egl-6 expression is predominantly neuronal, evidenced by transcriptional reporters and single-cell RNA-seq datasets.^30,39 However, low levels of egl-6 expression were detected in intestine-specific translation of ribosome-affinity purification, which may better reflect protein levels.⁴⁰ This suggests that FLP-17 may signal either through an intermediate cell type (such as a neuron) or directly to the intestine to activate UPR^ER.^30,39 Furthermore, the partial dependence, combined with persistent stress gene activation in egl-6 (lof) backgrounds (Figure 5 E), indicates that additional unidentified receptors and mechanisms likely contribute to FLP-17 phenotypes.

Although FLP-17 was sufficient to activate the UPR^ER, it was not required for cell non-autonomous activation of the UPR^ER by glial:: xbp-1s, as flp-17 null mutants did not suppress glial:: xbp-1s phenotypes. This likely reflects neuropeptide network redundancy. Supporting this hypothesis, flp-17 (lof)) resulted in modest upregulation of stress response genes (Figure S3G) and a slight increase in hsp-4p::GFP in the glial:: xbp-1s animals (Figure 2D), suggesting compensatory activation of stress signaling pathways when FLP-17 is absent. This compensation could occur through multiple mechanisms. First, glial:: xbp-1s may induce multiple neuropeptides that provide functionally redundant UPR^ER activation. While no other candidate from our neuropeptidomics screen was individually sufficient to induce UPR^ER, we cannot exclude compensation by peptides not detected in our analysis, such as insulin-like peptides.