Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila

One Sentence SummaryUpon microbial infection in Drosophila, the E3-ubiquitin ligase Hyd ubiquitinylates the NF-{kappa}B co-factor Akirin for its efficient binding to the NF-{kappa}B factor Relish and subsequent activation of immune effectors genes.\n\nABSTRACTThe Drosophila IMD pathway is activated upon microbial challenge with Gramnegative bacteria to trigger the innate immune response. In order to decipher this NF-{kappa}B signaling pathway, we undertook an ex-vivo RNAi screen targeting specifically E3 ubiquitin ligases and identified the HECT E3 ubiquitin ligase Hyperplastic Discs \"Hyd\" as a new actor of the IMD pathway. We showed that Hyd targets the NF-{kappa}B cofactor of Akirin. The K63-polyubiquitination chains deposited by Hyd decorate Akirin for its efficient binding to the NF-{kappa}B transcription factor Relish. We showed that this Hyd-mediated interaction is critical to activate immune-induced genes that depend on both Relish and Akirin, but is dispensable for those that depend solely on Relish. Therefore Hyd is key in operating a NF-{kappa}B transcriptional selectivity downstream of the IMD pathway. Drosophila depleted for Hyd or Akirin failed to express the full set of immune-induced anti-microbial peptide coding genes and succumbed to immune challenges. We showed further that Ubr5, the mammalian homolog of Hyd, is also required downstream of the NF-{kappa}B pathway for the IL1{beta}-mediated IL6 activation. This study links the action of a E3-ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.