The Oxidative Stress Response inCaenorhabditis elegansRequires the GATA Transcription Factor ELT-3 and SKN-1/Nrf2

Abstract

<p class="first" id="d6638816e212">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 ( <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00017144;class=Gene" id="d6638816e217" target="xrefwindow">BRAP-2</a>) 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 <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00017144;class=Gene" id="d6638816e222" target="xrefwindow">brap-2</a> </i> mutants display increased expression of <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00004804;class=Gene" id="d6638816e226" target="xrefwindow">SKN-1</a>-dependent, phase II detoxification enzymes that is dependent on <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00004055;class=Gene" id="d6638816e229" target="xrefwindow">PMK-1</a> (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 <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00004804;class=Gene" id="d6638816e236" target="xrefwindow">SKN-1</a> target <i> <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001752;class=Gene" id="d6638816e241" target="xrefwindow">gst-4</a> </i> in <i> <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00017144;class=Gene" id="d6638816e247" target="xrefwindow">brap-2</a> </i> mutants. We identified <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001251;class=Gene" id="d6638816e251" target="xrefwindow">ELT-3</a>, a member of the GATA transcription factor family, as a positive regulator of <i>gst-4p</i>:: <i>gfp</i> expression. We found that <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001251;class=Gene" id="d6638816e261" target="xrefwindow">ELT-3</a> interacts with <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00004804;class=Gene" id="d6638816e264" target="xrefwindow">SKN-1</a> to activate <i> <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001752;class=Gene" id="d6638816e269" target="xrefwindow">gst-4</a> </i> transcription <i>in vitro</i> and that <i> <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001251;class=Gene" id="d6638816e278" target="xrefwindow">elt-3</a> </i> is required for enhanced <i> <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001752;class=Gene" id="d6638816e285" target="xrefwindow">gst-4</a> </i> expression in the <i> <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00017144;class=Gene" id="d6638816e291" target="xrefwindow">brap-2</a>( <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBVar00092703;class=Variation" id="d6638816e294" target="xrefwindow">ok1492</a>) </i> mutant <i>in vivo</i>. Furthermore, nematodes overexpressing <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00004804;class=Gene" id="d6638816e301" target="xrefwindow">SKN-1</a> required <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001251;class=Gene" id="d6638816e304" target="xrefwindow">ELT-3</a> for life-span extension. Taken together, these results suggest a model where <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00017144;class=Gene" id="d6638816e307" target="xrefwindow">BRAP-2</a> acts as negative regulator of <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00004804;class=Gene" id="d6638816e311" target="xrefwindow">SKN-1</a> through inhibition of p38 MAPK activity, and that the GATA transcription factor <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00001251;class=Gene" id="d6638816e314" target="xrefwindow">ELT-3</a> is required along with <a data-untrusted="" href="http://www.wormbase.org/db/get?name=WBGene00004804;class=Gene" id="d6638816e317" target="xrefwindow">SKN-1</a> for the phase II detoxification response in <i>C</i> <i>. elegans</i>. </p>