Translation elongation defects activate the <i>Caenorhabditis elegans</i> ZIP-2 bZIP transcription factor-mediated toxin defense.

Abstract

The <i>Caenorhabditis elegans</i> bZIP transcription factor ZIP-2 is activated by toxins or mutations that inhibit translational elongation. The <i>zip-2</i> DNA-binding protein is encoded in a downstream main open reading frame (mORF), but under normal translation elongation conditions only an upstream overlapping oORF -1 frameshifted from mORF is translated. Mutations or toxins that slow translational elongation, but not inhibitors of translational initiation or termination, activate ZIP-2. An mORF initiation codon mutation does not disrupt the normal <i>zip-2</i> response to translational elongation defects, suggesting that <i>zip-2</i> activation does not depend on this ATG. An mORF early termination mutant can be activated by strong translation elongation inhibition, suggesting that translation initiated upstream on oORF +1 frameshifts when elongation is inhibited to the mORF reading frame downstream of the stop codon to activate a fused oORF/mORF ZIP-2 transcription factor. The protein and DNA sequences of <i>zip-2</i> oORF and mORF are conserved across the <i>Caenorhabditis</i>, suggesting selection for particular codons sensitive to translational elongation defects. Mutations that disrupt the oORF initiation codon constitutively activate <i>zip-2</i>, but not if the mORF initiation codon is also mutant, showing that <i>zip-2</i> oORF competes with mORF for translational initiation. oORF initiation codon mutation-activated <i>zip-2</i> slows <i>C. elegans</i> growth, and this slow growth is suppressed by a <i>zip-2</i> null mutation. A <i>zip-2</i> null mutant also strongly suppresses the growth arrest caused by translational elongation inhibitors. Thus, ZIP-2 is both a sensor of translational elongation attack, and a defense regulatory output via its activation of response genes.