Regulation of IL-1 production by an E2 ubiquitin conjugase

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Background: Our immune system defends us from infections. However, if the immune system is not properly regulated, it can initiate and perpetuate inflammation. Interleukin 1 (IL-1) is a protein that controls the immune system and problems in maintaining the right amount of IL-1 can be a cause for several chronic conditions. For example, IL-1 can cause fever and rashes in individuals genetically susceptible to hereditary fever syndromes. In addition, diseases such as arthritis (1.4 % UK population), diabetes (3.5 million present cases in the UK) and types of liver diseases, are also linked to IL-1 production triggered inflammation. Importantly, therapeutically blocking IL-1 improves symptoms in many diseased settings. However, as the use of these therapies expands, their limitations are also being recognised. It is therefore important to study how IL-1 and inflammation are regulated so that new and better interventions could be designed in the future. We recently identified that an enzyme (E2) regulates IL-1 production in human cells. E2 reduces IL-1 production, and its loss leads to elevated IL-1. However, how E2 regulates IL-1 remains unknown.Aims and hypotheses: In this proposal we wish to better understand how the E2 molecule works. We hypothesize that, (i) the E2 modifies IL-1 in a way that enhances their clearance, (ii) E2 activity is itself closely regulated, and (iii) genetic loss of E2 will lead to more severe inflammation. Experimental plan: We will use modern cellular and biochemical tools to elucidate how E2 regulates IL-1. Proteins that assist E2 in its IL-1-reducing effects will also be studied. We propose to use mice to study the effect of E2 on IL-1 and inflammatory disease. We will genetically engineering a mouse that will lack the gene encoding E2 from specific immune cells. We will study how these mice respond to a bacterial toxin that causes inflammation and conditions that mimic gouty arthritis. This genetic approach will provide a clear picture of how E2 works in immune cells that are the main producers of IL-1 in the body. In summary, our work should uncover how E2 affects IL-1 production and systemic inflammation. This work will have wide-ranging clinical and translational impact due to the causal link between IL-1 and the pathogenesis of many autoinflammatory diseases.