摘要：SummaryThe 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 inC. eleganstargeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that knockdown of the conserved amidohydrolaseT12A2.1/amdh-1activates 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.Graphical abstractDisplay OmittedHighlights•Genetic perturbation of amino acid catabolism pathways leads to SKN-1 activity•Nutrient sensing and signaling pathways are partially required•Buildup of a histidine catabolite (4-imidazolone-5-propionate) likely activates SKN-1•SKN-1 activation results in differential stress resilienceBiological sciences; Molecular biology; Transcriptomics
