UNRAVELING THE DUB NETWORK THAT CONTROLS DEATH RECEPTOR INDUCED CELL SURVIVAL AND DEATH PATHWAYS

解开控制死亡受体诱导的细胞存活和死亡途径的 DUB 网络

• 批准号: 414826869
• 负责人: Privatdozent Dr. Sjoerd van Wijk
• 金额: --
• 依托单位: Institut für Experimentelle Pädiatrische Hämatologie und Onkologie (EPHO)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414826869?language=en
• 关键词: UNRAVELING; DUB; NETWORK; CONTROLS; DEATH

Appropriate control of programmed cell death (e.g. apoptosis and necroptosis) and survival underlies embryonal development, innate immunity and cancer surveillance. Disturbances in these cell fate checkpoints affect the inflammatory state of the cellular microenvironment, but the molecular mechanisms how cells decide and switch between death/survival pathways remain poorly understood.Tumour necrosis factor (TNF) receptor 1 (TNFR1) is a prototypical death receptor and a central node in mediating apoptotic, necroptotic and survival responses. Post-translational modification of downstream TNFR substrate proteins with linear (M1) and K63-linked ubiquitin chains is essential for controlling these checkpoints and survival/death switching. M1/K63, as well as other chain types, are tightly regulated by deubiquitinating enzymes (DUBs), such as CYLD, OTULIN and A20.The individual roles of CYLD, OTULIN and A20 on M1/K63 ubiquitin in cell death/survival are relatively well understood. However, the interplay of CYLD/OTULIN/A20 in regulating ubiquitin-dependent cell fate checkpoints and switching remains largely unclear. Furthermore, numerous key proteins involved in cell death/survival are ubiquitinated as well, but regulatory DUBs for these crucial ubiquitination events remain unidentified. Therefore, a systemic approach to understand the complex DUB interplay will reveal novel insights into the vital control of cell survival/death responses. Overall, this proposal aims to unravel the OTULIN/CYLD/A20 triad in controlling TNFR1-mediated survival and programmed cell death pathways in mammalian cells and to investigate the contribution of additional DUBs on cell fate switching.The outcome of this proposal is expected to gain important novel insights in the fields of programmed cell death, innate immunology, infections and tumour formation. As a consequence, understanding the fundamental roles of ubiquitination in cell death and survival pathways will directly impact our understanding of human disease.

适当控制程序性细胞死亡（例如凋亡和坏死性凋亡）和存活是胚胎发育、先天免疫和癌症监测的基础。肿瘤坏死因子（TNF）受体1（TNFR 1）是一种典型的死亡受体，是介导细胞凋亡、坏死性凋亡和存活反应的中心节点。翻译后修饰的下游TNFR底物蛋白与线性（M1）和K63连接的泛素链是必不可少的控制这些检查点和生存/死亡开关。M1/K63以及其他链类型受到去泛素化酶（DUBs）如CYLD、OTULIN和A20的严格调控。CYLD、OTULIN和A20对M1/K63泛素在细胞死亡/存活中的单独作用相对较好地理解。然而，CYLD/OTULIN/A20在调节泛素依赖性细胞命运检查点和转换中的相互作用在很大程度上仍不清楚。此外，许多参与细胞死亡/存活的关键蛋白也被泛素化，但这些关键泛素化事件的调节DUB仍然未被确定。因此，了解复杂DUB相互作用的系统方法将揭示对细胞存活/死亡反应的重要控制的新见解。总体而言，该提案旨在解开OTULIN/CYLD/A20三联体在控制哺乳动物细胞中TNFR 1介导的存活和程序性细胞死亡途径中的作用，并研究额外DUB对细胞命运转换的贡献，该提案的结果有望在程序性细胞死亡，先天免疫学，感染和肿瘤形成等领域获得重要的新见解。因此，了解泛素化在细胞死亡和存活途径中的基本作用将直接影响我们对人类疾病的理解。