Role of Eicosanoids in Regulating the Ubiquitin Proteasome System and Proteostasis

The ubiquitin proteasome system (UPS) is a protein degradation mechanism in eukaryotes crucial to maintaining protein homeostasis, or proteostasis. There are tissue-specific differences in UPS activity and proteostasis, but the intercellular signaling mechanisms that mediate these differences are not well understood. This work examines eicosanoid signaling molecules—which are derived from polyunsaturated fatty acids (PUFAs)—and their role in proteostasis regulation, particularly the UPS. A reporter transgene that expresses the UbG76V-GFP chimeric protein, a metastable substrate for the UPS, is used in Caenorhabditis elegans epithelial cells to monitor the level of UPS activity. In wild-type nematodes, UbG76V-GFP levels remain high through 24 hours post L4 stage (L4+24). Then, levels decrease significantly due to increased UPS activity as the animals age and develop 48 hours past L4 (L4+48). Mutants for fat-1, a desaturase enzyme that converts ω-6 PUFAs to ω-3 PUFAs, exhibited elevated UbG76V-GFP turnover in the hypodermis even at the L4+24 stage, suggesting that either ω-6 PUFAs (or their eicosanoid derivatives) promote UPS activity or ω-3 PUFAs (or their eicosanoid derivatives) inhibit UPS activity. In the intestine, mutants for fat-1 showed reduced UbG76V-GFP turnover at the L4+24 and L4+48 life stages. Additionally, mutants for emb-8—an NADPH reductase needed to convert PUFAs into eicosanoids—also showed reduced UbG76V-GFP turnover in the hypodermis even at the L4+48 stage. These results suggest that elements of the eicosanoid signaling pathway, including ω-6 PUFAs and their derivatives, significantly contribute to regulation of the UPS and proteostasis.