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<p>Translation of the coding sequence for human C/EBP homologous protein (CHOP) is highly regulated by its upstream open reading frame (<i>uORF</i><sup><i>chop</i></sup>). ENDOU-1 was shown to play positive roles in mediating <i>CHOP</i> translation through suppressing <i>uORF</i><sup><i>chop</i></sup>-mediated translational inhibition (<i>uORF</i><sup><i>chop</i></sup>-MTI) during ER stress. However, when we screened for other RNA-binding proteins putatively engaged in the same inhibitory activity, we found that HnRNPA3 associated with zebrafish Endouc and its mammalian orthologue ENDOU-1 and could also be involved in <i>uORF</i><sup><i>chop</i></sup>-MTI in a p-eIF2α-independent manner. A time course experiment showed that the dynamic patterns of ENDOU-1, HnRNPA3 and CHOP were similarly fluctuant and positively correlated during ER stress. Moreover, overexpression of ENDOU-1 induced the increase of HnRNPA3 expression and caused a shift of HnRNPA3 from the nucleus to the cytoplasm. The resultant cytoplasmic HnRNPA3 served as a reader protein to recognize the N6-methyladenosine site on human <i>uORF</i><sup><i>chop</i></sup> cassette methylated by Wilms’ tumor 1-associating protein. Collectively, we suggest that HnRNPA3 is a positive effector of ENDOU-1 in an m6A-dependent manner, allowing it to reach maximal <i>CHOP</i> translation during ER stress.</p>

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ENDOU-1-induced cytoplasmic HnRNPA3 recognizes m6A methylation on the upstream reading frame of human CHOP transcripts to achieve maximal CHOP translation

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  • 发表日期：

    2026年3月28日

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  • Hung-Chieh Lee,
  • Yi-Hsin Huang,
  • Chi-Cheng Hsieh,
  • Yi-Nan Ke,
  • Huai-Jen Tsai

摘要

Translation of the coding sequence for human C/EBP homologous protein (CHOP) is highly regulated by its upstream open reading frame (uORFchop). ENDOU-1 was shown to play positive roles in mediating CHOP translation through suppressing uORFchop-mediated translational inhibition (uORFchop-MTI) during ER stress. However, when we screened for other RNA-binding proteins putatively engaged in the same inhibitory activity, we found that HnRNPA3 associated with zebrafish Endouc and its mammalian orthologue ENDOU-1 and could also be involved in uORFchop-MTI in a p-eIF2α-independent manner. A time course experiment showed that the dynamic patterns of ENDOU-1, HnRNPA3 and CHOP were similarly fluctuant and positively correlated during ER stress. Moreover, overexpression of ENDOU-1 induced the increase of HnRNPA3 expression and caused a shift of HnRNPA3 from the nucleus to the cytoplasm. The resultant cytoplasmic HnRNPA3 served as a reader protein to recognize the N6-methyladenosine site on human uORFchop cassette methylated by Wilms’ tumor 1-associating protein. Collectively, we suggest that HnRNPA3 is a positive effector of ENDOU-1 in an m6A-dependent manner, allowing it to reach maximal CHOP translation during ER stress.