|
Caspase-8 Products Available By Family |
|
| | |
| Two Opposing Biological Functions of Caspase-8: Apoptosis and Survival |
| Caspase-8 and the Extrinsic Apoptotic Pathway
Caspase-8 is a member of the cysteine-aspartic acid protease (caspase) family, and is unique among caspases in that it has two opposing biological functions: cell survival and cell death. Caspase-8 promotes cell death by triggering the extrinsic pathway of apoptosis. This is the most well known role of caspase-8. The extrinsic pathway begins when an appropriate ligand binds to and activates a death receptor. Death receptors reside in the membrane and are members of the TNF receptor superfamily. Binding of caspase-8 to a death receptor leads to recruitment and activation of the death-inducing signaling complex (DISC). DISC activation is a critical step for the initiation of the caspase cascade, which begins with caspase-8 activation.
Mechanism of DISC Activation: FADD, an adaptor molecule, caspase-8 and FLIP are all critical components of the DISC. FADD is recruited to the intracellular region of the ligand-bound death receptor where it binds to and activates caspase-8. Activated caspase-8 triggers downstream events resulting an apoptotic cell death. FLIP, a protein that resembles caspase-8 but lacks its catalytic site, acts as a caspase-8 antagonist and can inhibit caspase-8 apoptosis activity. It is interesting to note that is it thought that FLIP may have arisen after a duplication of the caspase-8 gene.
Death receptors activating caspase-8 include CD95 (APO-1, Fas), TRAIL-R1 (DR4), TRAIL-R2 (DR5), TNFR1 (p55/p60 TNFR), and TRAMP (DR3). These receptors are activated by their respective ligands: CD95L (APO-1L, FasL), TRAIL (Apo2L), TNF, and TL1A, respectively. These ligands belong to the TNF cytokine superfamily. Note: caspase-8 does not seem to be involved in DR6 death receptor signaling. |
|
 |
|
Caspase-8 blocks necrosis: A cell survival function. Non-apoptotic roles for caspases are increasingly being recognized. Caspase-8 in complex with FLIP and FADD blocks RIPK-dependent necrotic death. Although the precise mechanism remains to be fully elucidated, the deubiquitinase CYLD, RIPK1 and RIPK3 are all caspase-8 cleavage targets. Cleavage of any of these targets may be an essential factor in blocking necrosis. |
| Caspase-8 and Mitochondrial Apoptosis: The Bid Bridge
The apoptosis pathway has two arms – the extrinsic death receptor and the intrinsic mitochondrial. The intrinsic pathway is activated by diverse stimuli including DNA damage, UV or gamma radiation, chemotherapeutic drugs and growth factor withdrawal. These stimuli activate signaling pathways that culminate in mitochondrial permeabilization (MOMP), releasing proteins from the mitochondrial intermembrane which leads to apoptosis. Certain cell types activated by death receptors also require activation of the mitochondrial arm for apoptosis to occur. In this scenario, the Bcl-2 family member Bid bridges the extrinsic and intrinsic pathways. Caspase-8 activated at the DISC cleaves Bid into tBid, a pro-apoptotically active, truncated form of Bid, which initiates the mitochondrial apoptosis pathway. This leads to release of cytochrome c and Smac/DIABLO from the mitochondria resulting in apoptosis. Hence, DISC activated caspase-8 followed by caspse-8 mediated cleavage of Bid into tBid links death receptor stimulation and mitochondrial apoptotic events. Caspase-8 and Bid activation (cleavage of Bid into tBid) is an exciting area of cell death linking the extrinsic (death receptor) and intrinsic (mitochondrial) pathways which remains to be fully elucidated.
Caspase-8 and Survival Activity
Less well known, but increasingly gaining attention, is the role of caspase-8 in survival or non-apoptotic activities. For example, caspase-8 is required for embryonic development, T-lymphocyte activation and proliferation, and resistance to necrosis. Among the most intriguing is its role in protecting cells from necrosis. Doug Green has put forth the concept of caspase-8 and FLIP as the “Twins of Death and Protection” (2). Caspase-8, like other caspases, is synthesized as an inactive proform monomer. Upon activation, the proenzymes undergo proteolytic processing at conserved aspartic residues to produce two subunits, large (N-terminal, called p20) and small (C-terminal, called p10). The large and small subunits dimerize to form the active enzymes that contribute to cell death. Whereas caspase-8 homodimers induce apoptosis, caspase-8/FLIP heterodimers appear to have a protective effect and inhibit RIPK-dependent necrosis. Although it is known that caspase-8/FLIP heterodimers are catalytically active, and that caspase-8 acts in concert to block RIPK –dependent necrosis, the mechanism remains to be fully elucidated.
Caspase 8 Factoids · Caspase-8 orthologs have been identified in a number of mammals. Orthologs are genes in different species that evolved from a common ancestral gene by speciation, and typically retain the same function throughout the course of evolution. Hence it would be expected to have the same function among the various caspase-8 orthologs. Unique caspase-8 orthologs are present in birds.
· Caspase-8, caspase-2, caspase-9, and caspase-10 are initiator caspases which cleave effector caspases including caspase-3, caspase-6 and caspase-1, which in turn cleave other cellular proteins resulting in cellular demise and death. This is part of the central dogma in apoptosis which puts forth that sequential activation of caspases, or a caspase cascade, leads to the initiation and execution of apoptosis, resulting in cell death.
· Caspase-8 has been detected in the insoluble fraction of the brains from Huntington disease patients but not from normal controls, which suggests that it may have a role in neurodegenerative diseases.
· The caspase-8 gene maps on chromosome 2, at 2q33-q34. Many alternatively spliced transcript variants encoding different isoforms have been described. However not all variants have had their full-length sequences determined. Caspase-8 Tools
· Various caspase-8 antibodies and an siRNA Ready Gene are available for studying expression and the role of caspase-8 in apoptosis and other biological processes including development, immune cell proliferation and inhibition of necrosis.
· IMGENEX’s caspase-8 reagents have been widely published in the literature. Refer to the individual data sheets for additional information.
References
1. Caspase-8 and Bid: Caught in the act between death receptors and mitochondria. Kantari C, H Walczak. Biochima et Biophysica Acta 1813:558-563 (2011).
2. RIPK-dependent necrosis and it regulation by caspases: A mystery in five acts. Green DR, A Oberst, CP Dillon, R Weinlich, GS Salvesen. 44:9-116 (2011). | |
|
