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

Summary The 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 such as RELA also massively bind to gene bodies. Here, we demonstrate that the recruitment of RELA to intragenic regions regulates alternative splicing upon activation of NF-κB by the viral oncogene TAX of HTLV-1. Integrative analysis 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 a NF-kB activation-dependent manner, leading to alternative splicing of target exons thanks to DDX17 RNA helicase activity. This NF-kB/DDX17 axis accounts for a major part of the TAX-induced alternative splicing landscape that mainly affects genes involved in oncogenic pathways. 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.