SKN-1 regulates stress resistance downstream of amino catabolism pathways

• Main Authors: Bar-Ziv, R. (Author), Bolas, T. (Author), Dillin, A. (Author), Frankino, P.A (Author), Gildea, H.K (Author), Higuchi-Sanabria, R. (Author), Siddiqi, T.F (Author), Zhang, H. (Author)
• Format: Article
• Language: English
• Published: Elsevier Inc. 2022
• Subjects: Biological sciences; Molecular biology; Transcriptomics
• Online Access: View Fulltext in Publisher

 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. © 2022 The Author(s)