Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1
Lamya Ben Ameur, Paul Marie, Morgan Thénoz, Guillaume Giraud, Emmanuel Combe, Jean‐Baptiste Claude, Sébastien Lemaire, Nicolas Fontrodona, Hélène Polvèche, Marine Bastien, Antoine Gessain, Eric Wattel, Cyril F. Bourgeois, Didier Auboeuf, Franck Mortreux
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.