The Oxidative Stress Response in <i>Caenorhabditis elegans</i> Requires the GATA Transcription Factor ELT-3 and SKN-1/Nrf2

Abstract

Cellular damage caused by reactive oxygen species is believed to be a major contributor to age-associated diseases. Previously, we characterized the <i>Caenorhabditis elegans</i> Brap2 ortholog (BRAP-2) and found that it is required to prevent larval arrest in response to elevated levels of oxidative stress. Here, we report that <i>C. elegans brap-2</i> mutants display increased expression of SKN-1-dependent, phase II detoxification enzymes that is dependent on PMK-1 (a p38 MAPK <i>C. elegans</i> ortholog). An RNA-interference screen was conducted using a transcription factor library to identify genes required for increased expression of the SKN-1 target <i>gst-4</i> in <i>brap-2</i> mutants. We identified ELT-3, a member of the GATA transcription factor family, as a positive regulator of <i>gst-4p</i>::<i>gfp</i> expression. We found that ELT-3 interacts with SKN-1 to activate <i>gst-4</i> transcription <i>in vitro</i> and that <i>elt-3</i> is required for enhanced <i>gst-4</i> expression in the <i>brap-2(ok1492)</i> mutant <i>in vivo</i> Furthermore, nematodes overexpressing SKN-1 required ELT-3 for life-span extension. Taken together, these results suggest a model where BRAP-2 acts as negative regulator of SKN-1 through inhibition of p38 MAPK activity, and that the GATA transcription factor ELT-3 is required along with SKN-1 for the phase II detoxification response in <i>C</i><i>. elegans</i>.