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Monday 23 April 2018

CID seminar: Post-translational Regulation of Inflammasome-associated IL-1β, 24 April

Tuesday 24 April, 12-1pm, TRF seminar room 1

Presented by Dr James Vince, 
Laboratory head (Division: Inflammation), The Walter and Eliza Hall Institute

Cytosolic inflammasome protein complexes sense pathogen and sterile danger molecules to activate and induce the secretion of the potent proinflammatory cytokine interleukin-1β (IL-1β). The importance of IL-1β is underscored by clinical trials implicating its excessive activation in hereditary autoinflammatory syndromes, and common conditions such as gout, diabetes, cancer and cardiovascular disease. However, there remains a fundamental knowledge gap in our understanding of how IL-1β is regulated. Here we have used mass-spectrometry to investigate the post-translational targeting of IL-1β. We found that IL-1β is both phosphorylated and ubiquitylated on distinct residues. Mutation of a conserved IL-1β ubiquitylation site in vivo by CRISPR gene editing revealed how the ubiquitylation of IL-1β regulates IL-1β activation by inflammasome protein complexes. Moreover, we observed that innate immune stimuli can trigger IL-1β ubiquitylation to impact its activation.  Therefore the post-translational ubiquitylation of IL-1β may profoundly influence inflammatory disease outcomes.
The Vince laboratory studies how different programmed cell death signaling pathways influence inflammatory responses, with a particular interest in the regulation of inflammasome protein complexes. This research has discovered novel roles and mechanisms for the apoptotic and necroptotic cell death machinery in driving inflammasome activation following pathogen detection, and also in genetically acquired autoinflammatory conditions. Moreover, their work has uncovered how new classes of BH3-mimetics, designed to induce cancer cell death, may be re-purposed to kill pathogen-infected cells to eliminate damaging inflammation and promote pathogen clearance.

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