M1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila.

Anna Aalto, Aravind Mohan, Lukas Schwintzer, Sebastian Kupka, Christa Kietz, Henning Walczak, Meike Broemer, Annika Meinander

Research output: Contribution to journalArticleScientificpeer-review

27 Citations (Scopus)

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.
Original languageUndefined/Unknown
Pages (from-to)
JournalCell Death and Differentiation
DOIs
Publication statusPublished - 2018
MoE publication typeA1 Journal article-refereed

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