Translational readthrough, i.e., elongation of polypeptide chains beyond the stop codon, was initially reported for viral RNA, but later found also on eukaryotic transcripts, resulting in proteome diversification and protein‐level modulation. Here, we report that AGO1x, an evolutionarily conserved translational readthrough isoform of Argonaute 1, is generated in highly proliferative breast cancer cells, where it curbs accumulation of double‐stranded RNAs (dsRNAs) and consequent induction of interferon responses and apoptosis. In contrast to other mammalian Argonaute protein family members with primarily cytoplasmic functions, AGO1x exhibits nuclear localization in the vicinity of nucleoli. We identify AGO1x interaction with the polyribonucleotide nucleotidyltransferase 1 (PNPT1) and show that the depletion of this protein further augments dsRNA accumulation. Our study thus uncovers a novel function of an Argonaute protein in buffering the endogenous dsRNA‐induced interferon responses, different than the canonical function of AGO proteins in the miRNA effector pathway. As AGO1x expression is tightly linked to breast cancer cell proliferation, our study thus suggests a new direction for limiting tumor growth.

中文翻译：

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AGO1x预防dsRNA诱导的干扰素信号传导与乳腺癌细胞增殖有关。

最初报道了病毒RNA的翻译通读，即多肽链延伸超过终止密码子，但后来在真核转录本上也发现，导致蛋白质组多样化和蛋白质水平调节。在这里，我们报道在高度增殖的乳腺癌细胞中产生了AGO1x，它是一种进化上保守的Argonaute 1的翻译通读同种型，它抑制了双链RNA（dsRNA）的积累并因此诱导了干扰素反应和细胞凋亡。与主要具有胞质功能的其他哺乳动物Argonaute蛋白家族成员相反，AGO1x在核仁附近表现出核定位。我们确定与多核糖核苷酸核苷酸转移酶1（PNPT1）的AGO1x相互作用，并表明该蛋白的消耗进一步增加了dsRNA的积累。因此，我们的研究揭示了Argonaute蛋白在缓冲内源性dsRNA诱导的干扰素应答中的新功能，这与miRNA效应途径中AGO蛋白的规范功能不同。由于AGO1x的表达与乳腺癌细胞的增殖紧密相关，因此我们的研究提出了限制肿瘤生长的新方向。