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      A negative-feedback loop between the detoxification/antioxidant response factor SKN-1 and its repressor WDR-23 matches organism needs with environmental conditions.

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          Abstract

          Negative-feedback loops between transcription factors and repressors in responses to xenobiotics, oxidants, heat, hypoxia, DNA damage, and infection have been described. Although common, the function of feedback is largely unstudied. Here, we define a negative-feedback loop between the Caenorhabditis elegans detoxification/antioxidant response factor SKN-1/Nrf and its repressor wdr-23 and investigate its function in vivo. Although SKN-1 promotes stress resistance and longevity, we find that tight regulation by WDR-23 is essential for growth and reproduction. By disabling SKN-1 transactivation of wdr-23, we reveal that feedback is required to set the balance between growth/reproduction and stress resistance/longevity. We also find that feedback is required to set the sensitivity of a core SKN-1 target gene to an electrophile. Interestingly, the effect of feedback on target gene induction is greatly reduced when the stress response is strongly activated, presumably to ensure maximum activation of cytoprotective genes during potentially fatal conditions. Our work provides a framework for understanding the function of negative feedback in inducible stress responses and demonstrates that manipulation of feedback alone can shift the balance of competing animal processes toward cell protection, health, and longevity.

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          Author and article information

          Journal
          Mol. Cell. Biol.
          Molecular and cellular biology
          American Society for Microbiology
          1098-5549
          0270-7306
          Sep 2013
          : 33
          : 17
          Affiliations
          [1 ] Department of Biology and Genetics Institute, University of Florida, Gainesville, Florida, USA.
          Article
          MCB.00245-13
          10.1128/MCB.00245-13
          3753843
          23836880
          cd9357c1-17e1-454a-b713-e23ddc48c870
          History

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