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CASP8
CASP8 Full Name
Caspase 8
CASP8 Introduction
Caspase-8 is a member of the cysteine-aspartic acid protease (caspase) family. Caspase-8 is primarily considered a central initiator molecule in the apoptotic signaling pathway. The gene encoding CASP8 is in the 2q33-q34 region of human chromosome 2 and is responsible for translating a protein precursor known as pro-caspase-8, which contains two N-terminal Death Effector Domains (DEDs) and a protease domain. The canonical model for the initiation of extrinsic apoptotic signaling states that upon binding of a death receptor (such as Fas or TNFR1) to its ligand, FADD (Fas-Associated Death Domain) is recruited to the membrane. FADD is then able to recruit pro-caspase-8 by binding to each other's DED domains. This complex, known as the Death-Inducing Signaling Complex (DISC), forms a platform in which multiple pro-caspase-8 molecules come in close proximity and dimerize through "induced proximity" allowing for auto-cleavage and activation into a catalytically active heterotetramer. Active CASP8 then directly cleaves and activates the downstream executioner caspases (i.e. Caspase-3, Caspase-7) which commit the cell to the irreversible apoptotic program.
Figure 1. The activation of pro-Caspase-8 and DISC associated proteins. (Source: Mandal R, et al. 2020)
On the other hand, studies have shown that the activity state and conformation of CASP8, in essence, act as a molecular switch to decide the cell's fate into apoptosis, necroptosis, pyroptosis or survival. In some situations, when the apoptosis signaling pathway is blocked (e.g. through a high expression of IAP proteins or inhibition of Caspase-8 activity), death receptor signaling can be rerouted to induce a form of regulated cell necrosis that is programmed known as necroptosis. Necroptosis has been shown to typically require the formation of a cytoplasmic signaling complex called the "necrosome," which is largely made up of Receptor-Interacting Protein Kinase 1 (RIPK1) and RIPK3. In an unexpected twist, it has been found that fully active CASP8 can prevent necrosome formation and subsequent phosphorylation and activation of MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) by proteolytically cleaving RIPK1 and RIPK3, and thus preventing plasma membrane rupture and execution of necroptosis. In addition to governing distinct cell death pathways, the "promiscuity" of CASP8 is more widely represented in non-apoptotic cellular signaling, particularly in the immune and inflammatory responses. By interacting with a diverse range of signaling molecules, CASP8 delicately regulates cellular survival and functional states. CASP8 can modulate NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) signaling pathway, which is a central regulator of inflammation, immune responses and cell survival. For example, in a specific type of stimulation condition in T cells or macrophages, the CASP8 dimer can function as a scaffold protein, independently of its protease activity, to facilitate ubiquitination of RIPK1, thus leading to the activation of IKK complex, and the eventual activation of NF-κB and transcriptional expression of downstream inflammatory factors (such as TNF-α, IL-1β). This "scaffold" activity of CASP8, which is independent of its catalytic activity, uncovered a pro-inflammatory and immune cell activation-promoting property of CASP8.
On the contrary, CASP8's regulation of the inflammasome is even more complicated and paradoxical. For example, research has found that CASP8 can suppress the activity of the canonical NLRP3 inflammasome. Mechanistically, activated CASP8 may cleave and inactivate some of the components of the inflammasome complex or indirectly inhibit the signals that activate the NLRP3 inflammasome by inactivating the RIPK3-MLKL axis. However, under some conditions such as infection with certain pathogenic microorganisms (such as Yersinia, which can inhibit the canonical apoptotic pathway as well as NF-κB signaling), RIPK1 can also recruit and activate CASP8 to form a non-canonical inflammasome. It can directly activate Caspase-1 or the downstream protein GSDMD, thereby circumventing the canonical pathway to induce pyroptosis and release inflammatory cytokines. As an important effector that determines cell fate and mediates immune homeostasis, the malfunction of CASP8 is closely related to the pathogenesis and development of many human diseases. With respect to immune system diseases, loss-of-function mutations in the CASP8 gene cause a rare autosomal recessive disease-Caspase-8 Deficiency (CED, also known as Autoimmune Lymphoproliferative Syndrome Type IIB, ALPS-IIB). Afflicted patients show a variety of complex immune dysregulation syndromes, including splenomegaly, lymphadenopathy, autoimmunity (autoimmune cytopenias, etc. ), and susceptibility to some pathogens, especially viruses. The underlying mechanism is that the absence of CASP8 ablates the apoptosis ability of lymphocytes (especially activated T cells) in the death receptor pathway, leading to their abnormal proliferation and accumulation. Meanwhile, as CASP8 cannot effectively inhibit RIPK1/RIPK3-mediated necroptosis, excessive production of inflammatory cell death may occur under certain stimuli, which further promotes immune dysregulation. Furthermore, mutations in CASP8 have also been found to be associated with some autoinflammatory diseases. For instance, novel pathogenic mutations in CASP8 have been recently identified in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). These disease models unambiguously show that CASP8 is necessary for immune tolerance and anti-inflammation.
Alternate Names for CASP8
CASP8; caspase 8, apoptosis-related cysteine peptidase; caspase 8, apoptosis related cysteine protease; caspase-8; Casp 8; FLICE; MACH; MCH5; ALPS2B; Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 12 protein
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