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

iScience (Jul 2022)

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

Affiliations

Phillip A. Frankino: Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA; California Institute for Regenerative Medicine, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Talha F. Siddiqi: Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA; California Institute for Regenerative Medicine, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Theodore Bolas: Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA; California Institute for Regenerative Medicine, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Raz Bar-Ziv: Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA; California Institute for Regenerative Medicine, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Holly K. Gildea: Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA; California Institute for Regenerative Medicine, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Hanlin Zhang: Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA; California Institute for Regenerative Medicine, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Ryo Higuchi-Sanabria: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
Andrew Dillin: Howard Hughes Medical Institute University of California, Berkeley, CA 94720, USA; California Institute for Regenerative Medicine, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Corresponding author

Journal volume & issue: Vol. 25, no. 7
p. 104571

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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