Tyrosine catabolites influence SKN-1 signaling in a model of Type I Tyrosinemia.

Hereditary Tyrosinemia Type 1 (HT1) is a rare genetic disease that results from mutations of the tyrosine catabolism enzyme fumarylacetoacetate hydrolase (FAH) for which there is currently no cure. HT1 is successfully modeled in the nematode C. elegans , via mutations in the fumarylacetoacetate hydrolase ( fah-1 ) resulting in abnormalities in body size, intestinal degradation, and activation of SKN-1/NRF2. Previous work has shown that body size and intestinal phenotypes in this model may occur through the buildup of toxic tyrosine catabolites, although the mechanism by which SKN-1 becomes activated remains elusive. Here, we confirm previous findings that phenotypes in the HT1 model are dependent on upstream enzymes in this pathway. Notably, we find that fah-1 mediated SKN-1 activation is dependent on the upstream enzymes in this pathway, suggesting that an accumulation of tyrosine catabolites influence SKN-1 activity. Finally, we report that SKN-1 responds to knockdown of multiple tyrosine catabolism enzymes, suggesting that multiple catabolites act as signaling inputs to SKN-1 and that C. elegans are an appropriate model to study diseases related to tyrosine catabolism.

SKN-1 regulates stress resistance downstream of amino catabolism pathways.

The deleterious potential to generate oxidative stress is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and consequences of this remain unknown. Here, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that knockdown of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires ELT-3, NHR-49 and MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate. Activating SKN-1 results in increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 acts downstream of key catabolic pathways to influence physiology and stress resistance.