SKN-1 regulates stress resistance downstream of amino catabolism pathways

Phillip A Frankino; Talha F Siddiqi; Theodore Bolas; Raz Bar-Ziv; Holly K Gildea; Hanlin Zhang; Ryo Higuchi-Sanabria; Andrew Dillin

doi:10.1016/j.isci.2022.104571

SKN-1 regulates stress resistance downstream of amino catabolism pathways

iScience. 2022 Jun 9;25(7):104571. doi: 10.1016/j.isci.2022.104571. eCollection 2022 Jul 15.

Authors

Phillip A Frankino^{1

2

3}, Talha F Siddiqi^{1

2

3}, Theodore Bolas^{1

2

3}, Raz Bar-Ziv^{1

2

3}, Holly K Gildea^{1

2

4

3}, Hanlin Zhang^{1

2

3}, Ryo Higuchi-Sanabria⁵, Andrew Dillin^{1

2

4

3}

Affiliations

¹ Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA.
² California Institute for Regenerative Medicine, Berkeley, CA 94720, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
⁴ Helen Wills Neuroscience Institute, Berkeley, CA 94720, USA.
⁵ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

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.

Keywords: Biological sciences; Molecular biology; Transcriptomics.

Abstract

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