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bioRxiv · 10.1101/2022.02.03.479044

SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance

Frankino, P. A.·Siddiqi, T. F.·Bolas, T.·Bar-Ziv, R.·Gildea, H. K.·Zhang, H.·Higuchi-Sanabria, R.·Dillin, A.
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Abstract

The deleterious potential to generate oxidative stress and damage 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 physiological consequences of this remain unknown. To explore this connection, 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 genetic perturbation of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated detoxification genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires the GATA transcription factor ELT-3, nuclear hormone receptor NHR-49, and mediator complex subunit 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 (IP). Triggering SKN-1 activation results in a physiological trade off of increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 is a key surveillance factor which senses and responds to metabolic perturbations to influence physiology and stress resistance.

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Frankino, P. A., Siddiqi, T. F., Bolas, T., Bar-Ziv, R., Gildea, H. K., Zhang, H., Higuchi-Sanabria, R., Dillin, A.. 2022-02-03. SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance. https://doi.org/10.1101/2022.02.03.479044

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