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  • 标题:SKN-1 regulates stress resistance downstream of amino catabolism pathways
  • 本地全文:下载
  • 作者:Phillip A. Frankino ; Talha F. Siddiqi ; Theodore Bolas
  • 期刊名称:iScience
  • 印刷版ISSN:2589-0042
  • 出版年度:2022
  • 卷号:25
  • 期号:7
  • 页码:1-20
  • DOI:10.1016/j.isci.2022.104571
  • 语种:English
  • 出版社:Elsevier
  • 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
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