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Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1

Abstract : Chronic NF-κB activation in inflammation and cancer has long been linked to persistent activation of NF-κB-responsive gene promoters. However, NF-κB factors also massively bind to gene bodies. Here, we demonstrate that recruitment of the NF-κB factor RELA to intragenic regions regulates alternative splicing upon NF-κB activation by the viral oncogene Tax of HTLV-1. Integrative analyses of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17, in an NF-κB activation-dependent manner. This leads to alternative splicing of target exons due to the RNA helicase activity of DDX17. Similar results were obtained upon Tax-independent NF-κB activation, indicating that Tax likely exacerbates a physiological process where RELA provides splice target specificity. Collectively, our results demonstrate a physical and direct involvement of NF-κB in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-κB-related diseases.
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https://www.hal.inserm.fr/inserm-02877333
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Submitted on : Monday, June 22, 2020 - 11:39:50 AM
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Lamya Ben Ameur, Paul Marie, Morgan Thénoz, Guillaume Giraud, Emmanuel Combe, et al.. Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.3045. ⟨10.1038/s41467-020-16853-x⟩. ⟨inserm-02877333⟩

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