Biogenic Amine Neurotransmitters Promote Eicosanoid Production And Protein Homeostasis

Multicellular organisms use multiple pathways to restore protein homeostasis (proteostasis) in response to adverse physiological conditions, changing environment, and developmental aging. The nervous system can regulate proteostasis in different tissues, but it is unclear how it mobilizes proteostasis pathways to offset physiological decline. Here we show that C. elegans employs the humoral biogenic amine neurotransmitters dopamine, serotonin, and tyramine to regulate proteostasis and the activity of the Ubiquitin Proteasome System (UPS) in epithelial tissues. Mutants for biogenic amine synthesis show decreased poly-ubiquitination and turnover of a GFP-based UPS substrate. Using RNA-seq, we determined the expression profile of genes regulated by biogenic amine signaling. We find that biogenic amines promote the expression of a subset of cytochrome P450 monooxygenases involved in eicosanoid production from polyunsaturated fatty acids (PUFAs). Mutants for these P450s share the same UPS phenotype observed in biogenic amine mutants. The production of n-3 PUFAs is required for UPS substrate turnover, whereas mutants that accumulate n-3 PUFAs show accelerated turnover of this GFP-based substrate. Our results suggest that neurosecretory sensory neurons release biogenic amines to modulate the lipid signaling profile, which in turn activates stress response pathways to maintain proteostasis.