Lyall M, Pellegrini C, Yung T, Lopez-Castejon G. New insights into NLRP3 inflammasome regulation by ubiquitin. Poster presented at the British Society for Immunology Annual Congress; December 2014. Brighton, UK. [abstract] Immunology. 2014 Dec; 143(s2):96.

Macrophages sense tissue damage or infection, and initiate key inflammatory processes such as the activation of the inflammasome, a molecular complex whose assembly leads to the activation of caspase-1 and the release of the cytokine interleukin-1b (IL-1b). Inappropriate activation of the inflammasome contributes to deleterious inflammatory syndromes including hereditary periodic syndromes, diabetes, atherosclerosis and Alzheimer’s disease.

Dynamic post-translational modification of proteins with ubiquitin or ubiquitin like molecules such as SUMO or Nedd8, regulates a variety of signalling pathways necessary for the correct functioning of the cell. Ubiquitin binding is mediated by E1-E2-E3 enzymes whereas ubiquitin removal is catalysed by deubiquitinases (DUBs). DUBs, are involved in inflammasome regulation and are required for the activation of the NLRP3 inflammasome and the release of IL-1b. However, we are far from understanding how they regulate this process in response to tissue damage or infection.

Here we have investigated the effect of different inhibitors of the ubiquitin system in inflammasome activation in human macrophages (THP-1 and human blood derived macrophages). We have shown that the E1-ligase inhibitor PYR41 impairs IL-1b release activation in response to nigericin treatment, while MLN4924, a Nedd8-activating enzyme inhibitor had no effect, suggesting that the ubiquitin-like molecule Nedd8 is not involved in inflammasome regulation. We have also shown that USP7 inhibitors, HBX41108 and P22077, block NLRP3 inflammasome activation and pyroptosis, indicating a new role for this DUB in the inflammatory response. Further work is ongoing to elucidate the mechanisms by which USP7 controls this process in macrophages.

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