AGO1x prevents dsRNA-induced interferon signaling to promote breast cancer cell proliferation

Souvik Ghosh, Joao C Guimaraes, Manuela Lanzafame, Alexander Schmidt, Afzal Pasha Syed, Beatrice Dimitriades, Anastasiya Börsch, Shreemoyee Ghosh, Ana Luisa Correia, Johannes Danner, Gunter Meister, Luigi M. Terracciano, Salvatore Piscuoglio, and Mihaela Zavolan

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Apr 12, 2019
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Received Date: 29th March 19

Initially reported for viral RNA, elongation of polypeptide chains beyond the stop codon (translational readthrough (TR)) also occurs on eukaryotic transcripts. TR diversifies the proteome and can modulate protein levels 1–6. Here we report that AGO1x, a conserved TR isoform of Argonaute 1, is generated in highly proliferative breast cancer cells, where it curbs accumulation of double stranded RNAs, the induction of the interferon response and apoptosis. In contrast to other mammalian Argonaute protein family members with primarily cytoplasmic functions, AGO1x localizes to the nucleus, in the vicinity of nucleoli. We identify a novel interaction of AGO1x with the Polyribonucleotide Nucleotidyltransferase 1, depletion of either protein leading to dsRNA accumulation and impaired cell proliferation. Our study thus uncovers a novel function of an Argonaute protein outside of the miRNA effector pathway, in buffering dsRNA-induced interferon responses. As AGO1x expression is tightly linked to breast cancer cell proliferation, our study suggests a new direction for limiting tumor growth.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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