TY  - JOUR
AU  - Aalto, Anna L
AU  - Mohan, Aravind K
AU  - Schwintzer, Lukas
AU  - Kupka, Sebastian
AU  - Kietz, Christa
AU  - Walczak, Henning
AU  - Broemer, Meike
AU  - Meinander, Annika
TI  - M1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila.
JO  - Cell death and differentiation
VL  - 26
IS  - 5
SN  - 1350-9047
CY  - London
PB  - Macmillan
M1  - DZNE-2020-06957
SP  - 860-876
PY  - 2019
AB  - 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.
KW  - Animals
KW  - Bacterial Infections: genetics
KW  - Bacterial Infections: microbiology
KW  - Disease Models, Animal
KW  - Drosophila: genetics
KW  - Drosophila Proteins: genetics
KW  - Gram-Negative Bacteria: pathogenicity
KW  - Humans
KW  - Immunity, Innate: genetics
KW  - Inflammation: genetics
KW  - Inflammation: microbiology
KW  - Inhibitor of Apoptosis Proteins: genetics
KW  - Mouth: microbiology
KW  - Mouth: pathology
KW  - NF-kappa B: genetics
KW  - Protein Processing, Post-Translational: genetics
KW  - RNA-Binding Proteins: genetics
KW  - Signal Transduction: genetics
KW  - Transcription Factors: genetics
KW  - Ubiquitin: genetics
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Ubiquitination: genetics
LB  - PUB:(DE-HGF)16
C6  - pmid:30026495
C2  - pmc:PMC6462001
DO  - DOI:10.1038/s41418-018-0164-x
UR  - https://pub.dzne.de/record/140635
ER  -