RT Journal Article SR Electronic T1 Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila JF bioRxiv FD Cold Spring Harbor Laboratory SP 323170 DO 10.1101/323170 A1 Alexandre Cammarata-Mouchtouris A1 Xuan-Hung Nguyen A1 Akira Goto A1 Amir Orian A1 François Bonnay A1 Marie-Odile Fauvarque A1 Jean-Marc Reichhart A1 Nicolas Matt YR 2018 UL http://biorxiv.org/content/early/2018/05/16/323170.abstract AB Activation of inflammatory response is a tightly controlled process that is mediated by NF-κB pathways. Ubiquitinations are known to modulate the mammalian inflammatory response at all levels of the NF-κB pathways, but the mechanism involved in this ubiquitin-mediated modulation of the inflammation is still not fully understood. Here, we used Drosophila genetics to identify E3-ubiquitin ligases involved in the innate immune response and explore their conservation in mammals. To this aim, we conducted an ex-vivo RNA interference screen of the E3 ubiquitin-ligases encoded by the fruit fly genome downstream of the Drosophila IMD pathway. This screen identified Hyperplastic Discs “Hyd” as acting genetically at the level of the NF-κB cofactor Akirin. Drosophila lacking Hyd failed to express the full set of anti-microbial peptides coding genes and succumbed to immune challenges. Remarkably, HyD-mediated K63-polyubiquitination of Akirin is required for the efficient binding of Akirin to the NF-κB transcription factor Relish. This Hyd-mediated interaction triggers the activation of a subset of Relish target genes, required in-vivo to survive immune challenges. We show further that Urb5, the mammalian homolog of Hyd, is also required in the NF-κB pathway. 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.