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

Abstract

The chronic NF-{kappa}B activation in inflammation and cancer has long been linked to persistent activation of NF-{kappa}B responsive gene promoters. However, NF-{kappa}B 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-{kappa}B 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-{kappa}B in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-{kappa}B-related diseases.