Regulation of IL-1 production by an E2 ubiquitin conjugase

E2 泛素缀合酶对 IL-1 产生的调节

• 批准号: MR/P022138/1
• 负责人: Avinash Shenoy
• 金额: $ 62.4万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP022138%2F1
• 关键词: Regulation; IL; production; E2; ubiquitin

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.

背景：我们的免疫系统保护我们免受感染。然而，如果免疫系统没有得到适当的调节，它可能会引发和延续炎症。白介素1(IL-1)是一种控制免疫系统的蛋白质，维持适量的IL-1的问题可能是几种慢性病的原因。例如，IL-1可导致遗传易感遗传性发热综合征的人发烧和皮疹。此外，关节炎(占英国人口的1.4%)、糖尿病(英国现有病例350万例)和各种肝病等疾病也与IL-1的产生引发炎症有关。重要的是，通过治疗阻断IL-1可以改善许多疾病环境中的症状。然而，随着这些疗法的使用范围扩大，它们的局限性也被认识到了。因此，重要的是研究IL-1和炎症是如何调节的，以便将来能够设计出新的、更好的干预措施。我们最近发现了一种酶(E2)，它能调节人类细胞中IL-1的产生。雌二醇会减少IL-1的产生，它的缺失会导致IL-1的升高。然而，E2如何调节IL-1仍然是未知的。目的和假设：在这个建议中，我们希望更好地了解E2分子是如何工作的。我们假设，(I)E2以一种增强其清除性的方式修改IL-1，(Ii)E2活动本身受到密切调控，(Iii)E2的遗传缺失将导致更严重的炎症。实验计划：我们将使用现代细胞和生化工具来阐明E2是如何调节IL-1的。帮助E2降低IL-1效果的蛋白质也将被研究。我们建议用小鼠来研究E2对IL-1和炎症性疾病的影响。我们将用基因工程技术改造一只小鼠，使其缺乏特定免疫细胞的E2编码基因。我们将研究这些小鼠对一种细菌毒素的反应，这种细菌毒素会导致炎症和模拟痛风性关节炎的情况。这种遗传方法将清楚地描绘出E2是如何在免疫细胞中发挥作用的，而免疫细胞是体内产生IL-1的主要来源。总而言之，我们的工作应该揭示E2是如何影响IL-1的产生和全身炎症的。这项工作将具有广泛的临床和翻译影响，因为IL-1与许多自身炎症性疾病的发病机制之间存在因果联系。

项目成果

Cyclic nucleotides, gut physiology and inflammation.

• DOI: 10.1111/febs.15198
• 发表时间: 2020-05
• 期刊: The FEBS journal
• 作者: Prasad H;Shenoy AR;Visweswariah SS
• 通讯作者: Visweswariah SS

Very long O-antigen chains of Salmonella Paratyphi A inhibit inflammasome activation and pyroptotic cell death.

• DOI: 10.1111/cmi.13306
• 发表时间: 2021-05
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Mylona E;Sanchez-Garrido J;Hoang Thu TN;Dongol S;Karkey A;Baker S;Shenoy AR;Frankel G
• 通讯作者: Frankel G

A Probe for NLRP3 Inflammasome Inhibitor MCC950 Identifies Carbonic Anhydrase 2 as a Novel Target.

• DOI: 10.1021/acschembio.1c00218
• 发表时间: 2021-06-18
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Kennedy CR;Goya Grocin A;Kovačič T;Singh R;Ward JA;Shenoy AR;Tate EW
• 通讯作者: Tate EW