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

适当控制程序性细胞死亡(如细胞凋亡和坏死性下垂)和存活是胚胎发育、先天免疫和癌症监测的基础。这些细胞命运检查点的紊乱影响细胞微环境的炎症状态，但细胞如何决定和在死亡/生存途径之间切换的分子机制尚不清楚。肿瘤坏死因子受体1(TNFR1)是典型的死亡受体，也是介导细胞凋亡、坏死和生存反应的中心节点。下游TNFR底物蛋白的线状(M1)和K63连接的泛素链的翻译后修饰对于控制这些检查点和生存/死亡切换是必不可少的。M1/K63以及其他链类型都受到去泛素化酶(DUB)的严格调控，如CyLD、OTULIN和A20。CyLD、OTULIN和A20在M1/K63泛素上的单独作用相对较好地被理解。然而，CyLD/OTULIN/A20在调节泛素依赖的细胞命运检查点和开关方面的相互作用仍然很大程度上仍不清楚。此外，许多参与细胞死亡/生存的关键蛋白也是泛素化的，但这些关键的泛素化事件的调控配对仍然不确定。因此，一种系统的方法来理解复杂的配音相互作用将揭示对细胞生存/死亡反应的关键控制的新见解。总之，本研究旨在揭示OTULIN/CyLD/A20三联体在哺乳动物细胞中控制TNFR1介导的细胞存活和程序性死亡途径，并研究额外的DUBS在细胞命运转换中的作用。本研究的结果有望在细胞程序性死亡、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生存途径中的基本作用将直接影响我们对人类疾病的理解。

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.