engAalto, Anna LMohan, Aravind KSchwintzer, LukasKupka, SebastianKietz, ChristaWalczak, HenningBroemer, MeikeMeinander, AnnikaM1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila.info:eu-repo/classification/ddc/610AnimalsBacterial Infections: geneticsBacterial Infections: microbiologyDisease Models, AnimalDrosophila: geneticsDrosophila Proteins: geneticsGram-Negative Bacteria: pathogenicityHumansImmunity, Innate: geneticsInflammation: geneticsInflammation: microbiologyInhibitor of Apoptosis Proteins: geneticsMouth: microbiologyMouth: pathologyNF-kappa B: geneticsProtein Processing, Post-Translational: geneticsRNA-Binding Proteins: geneticsSignal Transduction: geneticsTranscription Factors: geneticsUbiquitin: geneticsUbiquitin-Protein Ligases: geneticsUbiquitination: geneticsPost-translational modifications such as ubiquitination play a key role in regulation of inflammatory nuclear factor-κB (NF-κB) signalling. The Drosophila IκB kinase γ (IKKγ) Kenny is a central regulator of the Drosophila Imd pathway responsible for activation of the NF-κB Relish. We found the Drosophila E3 ligase and HOIL-1L interacting protein (HOIP) orthologue linear ubiquitin E3 ligase (LUBEL) to catalyse formation of M1-linked linear ubiquitin (M1-Ub) chains in flies in a signal-dependent manner upon bacterial infection. Upon activation of the Imd pathway, LUBEL modifies Kenny with M1-Ub chains. Interestingly, the LUBEL-mediated M1-Ub chains seem to be targeted both directly to Kenny and to K63-linked ubiquitin chains conjugated to Kenny by DIAP2. This suggests that DIAP2 and LUBEL work together to promote Kenny-mediated activation of Relish. We found LUBEL-mediated M1-Ub chain formation to be required for flies to survive oral infection with Gram-negative bacteria, for activation of Relish-mediated expression of antimicrobial peptide genes and for pathogen clearance during oral infection. Interestingly, LUBEL is not required for mounting an immune response against systemic infection, as Relish-mediated antimicrobial peptide genes can be expressed in the absence of LUBEL during septic injury. Finally, transgenic induction of LUBEL-mediated M1-Ub drives expression of antimicrobial peptide genes and hyperplasia in the midgut in the absence of infection. This suggests that M1-Ub chains are important for Imd signalling and immune responses in the intestinal epithelia, and that enhanced M1-Ub chain formation is able to drive chronic intestinal inflammation in flies.Cell death and differentiation 26(5), 860-876 (2018). doi:10.1038/s41418-018-0164-xinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionMacmillan2019info:eu-repo/semantics/closedAccessDEhttps://pub.dzne.de/record/140635https://pub.dzne.de/search?p=id:%22DZNE-2020-06957%22Researchersinfo:eu-repo/semantics/altIdentifier/pmid/pmid:30026495info:eu-repo/semantics/altIdentifier/issn/1350-9047info:eu-repo/semantics/altIdentifier/issn/1476-5403info:eu-repo/semantics/altIdentifier/doi/10.1038/s41418-018-0164-x