Translation elongation defects activate the Caenorhabditis elegans ZIP-2 bZIP transcription factor-mediated toxin defense

• 成果类型: Article
• 署名作者: Kniazeva, Marina; Ruvkun, Gary
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15071
• DOI: 10.1073/pnas.2423578122
• 发表日期: 2025-02-11
• 关键词: hygromycin-b inhibition; messenger-rna; inactivation; reinitiation; SURVEILLANCE; suppression; target

摘要

The Caenorhabditis elegans bZIP transcription factor ZIP- 2 is activated by toxins or mutations that inhibit translational elongation. The zip- 2 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 zip- 2 response to translational elongation defects, suggesting that zip- 2 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 zip- 2 oORF and mORF are conserved across the Caenorhabditis, suggesting selection for particular codons sensitive to translational elongation defects. Mutations that disrupt the oORF initiation codon constitutively activate zip- 2, but not if the mORF initiation codon is also mutant, showing that zip- 2 oORF competes with mORF for translational initiation. oORF initiation codon mutation- activated zip- 2 slows C. elegans growth, and this slow growth is suppressed by a zip- 2 null mutation. A zip- 2 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.