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

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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.