# CASP8

## Overview
CASP8 is a gene that encodes the protein caspase 8, a cysteine-aspartic acid protease that plays a pivotal role in the regulation of apoptosis, necroptosis, and inflammation. Caspase 8 is categorized as an initiator caspase, primarily involved in the extrinsic apoptotic pathway, where it is activated by death receptors such as TNFR1 and FAS. Upon activation, caspase 8 initiates a cascade of downstream events leading to cell death by activating executioner caspases. Additionally, caspase 8 functions as a regulatory molecule in necroptosis by cleaving key pro-necroptotic proteins, thereby inhibiting this form of programmed necrotic cell death. Beyond its roles in cell death, caspase 8 is involved in modulating inflammatory responses and NF-κB signaling, highlighting its multifaceted role in maintaining cellular homeostasis and immune regulation (Salvesen2014Functions; Orning2020Multiple; Han2021Regulation).

## Structure
Caspase 8 (CASP8) is a cysteine-aspartic acid protease involved in apoptosis, characterized by its structural complexity. The primary structure of CASP8 includes an N-terminal tandem death effector domain (DED) and a C-terminal catalytic protease domain. The DEDs facilitate homotypic interactions with partner proteins, such as Fas-associated death domain protein (FADD) in the death-inducing signaling complex (DISC) (Shen2015Crystal).

The secondary structure of CASP8 features alpha-helices and beta-sheets, forming a homodimer essential for its activation. The tertiary structure involves the formation of a tandem DED filament, which is crucial for the assembly and regulation of the DISC. This filament is composed of two DEDs with limited sequence identity, forming complex interstrand interactions essential for filament assembly (Fu2016CryoEM).

In its quaternary structure, CASP8 forms a filament-like structure when complexed with FADD, characterized by a triple helix core formed by tandem DEDs. This structure facilitates the dimerization and activation of CASP8's catalytic domains (Fox2021Cryo-EM). Post-translational modifications, such as phosphorylation and cleavage, regulate CASP8 activity, and splice variants can alter its function and localization. The recruitment of c-FLIP S into the complex inhibits CASP8 activity by altering the tDED triple helix architecture, preventing catalytic domain assembly and filament elongation (Fox2021Cryo-EM).

## Function
Caspase-8 (CASP8) is a multifunctional enzyme that plays a critical role in regulating various cell death pathways and inflammation processes in healthy human cells. It is primarily known for initiating extrinsic apoptosis through the activation of death receptors such as TNFR1 and FAS, leading to the activation of downstream executioner caspases like caspase-3, -6, and -7, which ultimately result in cell death (Han2021Regulation). CASP8 also inhibits necroptosis, a form of inflammatory cell death, by cleaving pro-necroptotic molecules such as RIPK1 and RIPK3, preventing the formation of necrosomes (Salvesen2014Functions; Orning2020Multiple).

Beyond its role in apoptosis and necroptosis, CASP8 is involved in modulating inflammation by activating inflammasomes and processing cytokines like IL-1β (Han2021Regulation). It also regulates NF-κB activation, which is essential for proper lymphocyte activation and cytokine production (Han2021Regulation). CASP8's activity is crucial for maintaining cellular homeostasis, as its absence can lead to spontaneous inflammation and is associated with conditions like inflammatory bowel disease (Han2021Regulation). CASP8 functions as both a pro-inflammatory and anti-inflammatory regulator, depending on the cellular context (Han2021Regulation).

## Clinical Significance
Mutations and alterations in the CASP8 gene are associated with a variety of diseases and conditions. Caspase-8 deficiency, resulting from mutations in the CASP8 gene, can lead to rare immunological diseases characterized by symptoms such as failure to thrive, organomegaly, and very early-onset inflammatory bowel disease (VEO-IBD). These conditions are often linked to immune system dysregulation (Bazgir2023A).

In cancer, CASP8 mutations and altered expression levels play a significant role. Inactivating mutations have been reported in colorectal carcinoma and head and neck squamous cell carcinoma, contributing to tumor resistance to apoptosis. Epigenetic silencing of the CASP8 promoter is observed in various cancers, including medulloblastoma and breast cancer, facilitating cancer progression by helping cells evade apoptosis (Contadini2023Caspase-8; Mandal2020Caspase-8:).

CASP8 is also implicated in autoimmune disorders. A homozygous mutation in CASP8 is linked to Autoimmune Lympho-Proliferative Syndrome (ALPS), characterized by splenomegaly, lymphadenopathy, and resistance to FAS-mediated apoptosis. This mutation disrupts the negative selection of autoreactive T-cells, leading to immune dysregulation (Mandal2020Caspase-8:). 

Overall, CASP8 mutations and dysregulation can lead to significant clinical consequences, affecting apoptosis and immune responses.

## Interactions
Caspase-8 (CASP8) is involved in several critical protein interactions that regulate apoptosis and other cellular processes. It interacts with the Fas-associated death domain (FADD) to form the death-inducing signaling complex (DISC), which is essential for its activation in the extrinsic apoptotic pathway (Kantari2011Caspase8; Muzio1998An). Caspase-8 also forms a complex with FLIP (FLICE-like inhibitory protein), which is crucial for inhibiting RIPK3-dependent necrosis, a form of programmed necrotic cell death. This interaction prevents the formation of a stable complex involving FADD, RIPK1, and RIPK3, thereby suppressing necrosis (Oberst2011Catalytic).

Caspase-8 is also involved in NF-κB signaling. It interacts with the Bcl10-MALT1 complex, which is necessary for recruiting and activating the IKK complex, a key component in the NF-κB pathway (Su2005Requirement). In cancer, caspase-8 can be phosphorylated on Tyr380, which inhibits its apoptotic function and promotes interactions with proteins through the SH2 domain, affecting cell migration and transformation (Contadini2023Caspase-8). These interactions highlight caspase-8's multifaceted role in regulating cell death and survival pathways.


## References


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