Mechanisms of Caspase-8/cFLIP heterodimer-mediated cell death regulation in homeostatic and pathological conditions

• Applicant: Alessandro Annibaldi, Ph.D.
• Subject Area: Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458975342

The ability of multicellular organisms to preserve tissue integrity and overcome stress-induced damage tightly depends on cell death regulation. The maintenance of homeostatic conditions requires specific cell death-suppression mechanisms, the abrogation of which results in tissue damage with fatal consequences for the organism. On the other hand, the recovery from damage caused by different types of insults, such as pathogen infections or injury, requires mechanisms that control the extent of cell death. Their failure interferes with the execution of tissue repair programs, exacerbating the pathological conditions. The Caspase-8/cFLIP heterodimer is a signalling module downstream of immune receptors, including TNFR1, that can both suppress and modulate cell death programs. It is therefore indispensable to control cell death under both physiological and pathological conditions However, the mechanisms by which this occurs are still poorly understood. Here, by making use of novel as well as established mouse models, we investigate the molecular mechanisms by which the coordinated proteolysis of Caspase-8 and cFLIP contributes to the regulation of cell death responses in pathological conditions. In addition, we aim to elucidate how cFLIP orchestrates the suppression of cell death responses in the intestine, to guarantee tissue integrity and function. The findings coming from this research proposal will help understand how cells and tissues coordinate different cell death programs to maintain homeostatic conditions and overcome damage.

• DFG Programme: Research Grants