%0 Journal Article
%A Aalto, Anna L
%A Mohan, Aravind K
%A Schwintzer, Lukas
%A Kupka, Sebastian
%A Kietz, Christa
%A Walczak, Henning
%A Broemer, Meike
%A Meinander, Annika
%T M1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila.
%J Cell death and differentiation
%V 26
%N 5
%@ 1350-9047
%C London
%I Macmillan
%M DZNE-2020-06957
%P 860-876
%D 2019
%X Post-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.
%K Animals
%K Bacterial Infections: genetics
%K Bacterial Infections: microbiology
%K Disease Models, Animal
%K Drosophila: genetics
%K Drosophila Proteins: genetics
%K Gram-Negative Bacteria: pathogenicity
%K Humans
%K Immunity, Innate: genetics
%K Inflammation: genetics
%K Inflammation: microbiology
%K Inhibitor of Apoptosis Proteins: genetics
%K Mouth: microbiology
%K Mouth: pathology
%K NF-kappa B: genetics
%K Protein Processing, Post-Translational: genetics
%K RNA-Binding Proteins: genetics
%K Signal Transduction: genetics
%K Transcription Factors: genetics
%K Ubiquitin: genetics
%K Ubiquitin-Protein Ligases: genetics
%K Ubiquitination: genetics
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30026495
%2 pmc:PMC6462001
%R 10.1038/s41418-018-0164-x
%U https://pub.dzne.de/record/140635