In vivo analysis of the role of cFLIP in the regulation of caspase-8 and its functions in apoptosis, necroptosis and inflammation

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Cell death is a physiological process with important functions in tissue homeostasis, immunity and inflammation. Apoptosis is the best characterised type of cell death induced by a family of proteases termed caspases. Caspase-8 induces apoptosis in the extrinsic pathway activated downstream of death receptors of the TNF receptor superfamily. In addition to its role in inducing extrinsic apoptosis, caspase-8 has a critical function in preventing the activation of necroptosis, a recently discovered pathway of regulated necrotic cell death induced by RIPK3 and its substrate MLKL. Necroptosis is a lytic type of cell death that induces inflammation due to the rapid release of cellular components (termed danger associated molecular patterns, DAMPs) activating immune responses in bystander cells. During apoptosis, the plasma membrane remains intact thus restricting DAMP release and preventing inflammation. Therefore, its dual function in controlling both apoptosis and necroptosis makes caspase-8 a critical regulator of tissue homeostasis, immunity and inflammation. Caspase-8 activity is regulated by cFLIP, a protein sharing remarkable similarity with caspase-8 but lacking catalytic activity. Several studies provided evidence that interaction of cFLIP with caspase-8 critically controls apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here we aim to assess the mechanisms by which cFLIP regulates caspase-8 activity and controls tissue homeostasis and inflammation using genetic, molecular and biochemical methodologies.