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| Home > Publications Database > M1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila. |
| Home > Publications Database > M1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila. |
| Journal Article | DZNE-2020-06957 |
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2019
Macmillan
London
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Please use a persistent id in citations: doi:10.1038/s41418-018-0164-x
Abstract: 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.
Keyword(s): Animals (MeSH) ; Bacterial Infections: genetics (MeSH) ; Bacterial Infections: microbiology (MeSH) ; Disease Models, Animal (MeSH) ; Drosophila: genetics (MeSH) ; Drosophila Proteins: genetics (MeSH) ; Gram-Negative Bacteria: pathogenicity (MeSH) ; Humans (MeSH) ; Immunity, Innate: genetics (MeSH) ; Inflammation: genetics (MeSH) ; Inflammation: microbiology (MeSH) ; Inhibitor of Apoptosis Proteins: genetics (MeSH) ; Mouth: microbiology (MeSH) ; Mouth: pathology (MeSH) ; NF-kappa B: genetics (MeSH) ; Protein Processing, Post-Translational: genetics (MeSH) ; RNA-Binding Proteins: genetics (MeSH) ; Signal Transduction: genetics (MeSH) ; Transcription Factors: genetics (MeSH) ; Ubiquitin: genetics (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Ubiquitination: genetics (MeSH)
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