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

ABSTRACT

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.