Caspase 8

Caspase 8

Caspase 8 is a cysteine-aspartic acid protease that plays a crucial role in the apoptosis signaling pathways. It is an initiator caspase, meaning it is one of the first caspases activated in the cascade that leads to programmed cell death. Caspase 8 is encoded by the CASP8 gene in humans.

Structure

Caspase 8 is synthesized as an inactive proenzyme, which is then cleaved to form the active enzyme. The active form of caspase 8 consists of two large and two small subunits that form a heterotetramer. The enzyme contains a death effector domain (DED) that is important for its recruitment to the death-inducing signaling complex (DISC).

Function

Caspase 8 is primarily involved in the extrinsic pathway of apoptosis. It is activated by death receptors such as Fas receptor and TNF receptor. Upon activation, caspase 8 cleaves and activates downstream effector caspases, such as caspase 3, leading to the execution phase of apoptosis.

Diagram of TNF signaling pathway involving caspase 8.

Role in Apoptosis

Caspase 8 is recruited to the DISC upon ligand binding to death receptors. This recruitment is mediated by the interaction of the DEDs of caspase 8 with the adaptor protein FADD (Fas-associated death domain). Once at the DISC, caspase 8 is activated through dimerization and autocatalytic cleavage.

Role in Necroptosis

In addition to its role in apoptosis, caspase 8 can inhibit necroptosis, a form of programmed necrosis. Caspase 8 cleaves and inactivates the kinase RIPK1 and RIPK3, which are essential for the execution of necroptosis.

Pathways

Caspase 8 is a key component of several signaling pathways, including the extrinsic apoptosis pathway and the TNF signaling pathway.

Overview of signal transduction pathways including apoptosis.

Clinical Significance

Mutations or dysregulation of caspase 8 can lead to various diseases. For example, reduced caspase 8 activity is associated with certain cancers, as it can lead to decreased apoptosis and increased cell survival. Conversely, excessive activation of caspase 8 can contribute to neurodegenerative diseases and other conditions characterized by excessive cell death.

Related Pages

• Apoptosis
• Caspase
• Death receptor
• Fas receptor
• TNF receptor