The <i>Caenorhabditis elegans</i> Oxidative Stress Response Requires the NHR-49 Transcription Factor

Abstract

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that <i>C. elegans</i> BRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as <i>gst-4</i>, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce <i>gst-4</i> expression in <i>brap-2(ok1492)</i> mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of <i>nhr-49</i> suppresses the activation of <i>gst-4</i> caused by <i>brap-2</i> inactivation and that gain-of-function alleles of <i>nhr-49</i> promote <i>gst-4</i> expression. We also demonstrate that <i>nhr-49</i> and its cofactor <i>mdt-15</i> are required to express phase II detoxification enzymes upon exposure to chemicals that induce oxidative stress. Furthermore, we show that NHR-49 and MDT-15 enhance expression of <i>skn-1a/c</i> These findings identify a novel role for NHR-49 in ROS detoxification by regulating expression of SKN-1C and phase II detoxification genes.