Search results for CASP8

Showing 19 results out of 45

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Interactor (3 results from a total of 3)

Identifier: Q14790-2
Species: Homo sapiens
Primary external reference: UniProt: Q14790-2
Identifier: Q14790-5
Species: Homo sapiens
Primary external reference: UniProt: Q14790-5
Identifier: Q14790-1
Species: Homo sapiens
Primary external reference: UniProt: Q14790-1

Protein (4 results from a total of 16)

Identifier: R-HSA-57031
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: CASP8: Q14790
Identifier: R-HSA-933456
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: CASP8: Q14790
Identifier: R-HSA-3465404
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q14790
Identifier: R-HSA-75975
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q14790

Reaction (4 results from a total of 18)

Identifier: R-HSA-9693929
Species: Homo sapiens
Compartment: cytosol
Activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) controls tumor necrosis factor receptor (TNFR)- and pattern recognition receptors-mediated apoptosis, necroptosis and inflammatory pathways. RIPK1 activity is regulated post-translationally by ubiquitylation and phosphorylation events, as well as by caspase-8 (CASP8)-mediated cleavage. CASP8 facilitates the cleavage of human and mouse RIPK1 after residues D324 and D325, respectively and prevents caspase-8-dependent apoptosis and RIPK1:RIPK3-dependent necroptosis (Lin Y et al. 1999; Hopkins-Donaldson S et al. 2000; Newton K et al. 2019; Zhang X et al. 2019; Lalaoui N et al. 2020). The dominantly inherited mutations D324N, D324H, D324V and D324Y in RIPK1 prevent CASP8 from cleaving the mutated protein, thereby promoting activation of RIPK1 and leading to an autoinflammatory response in humans (Tao P et al. 2020; Lalaoui N et al. 2020).
Identifier: R-HSA-5357828
Species: Homo sapiens
Compartment: cytosol
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can be a part of cell death and survival signaling complexes. Whether RIPK1 functions in apoptosis, necroptosis or NFκB signaling is dependent on autocrine/paracrine signals, on the cellular context and tightly regulated by posttranslational modifications of RIP1 itself. The pro-survival function of RIPK1 is achieved by polyubiquitination which is required for recruitment of signaling molecules/complexes such as the IKK complex and the TAB2:TAK1 complex to mediate activation of NFκB signaling (Ea CK et al. 2006). CYLD-mediated deubiquitination of RIPK1 switches its pro-survival function to caspase-mediated pro-apoptotic signaling (Fujikura D et al. 2012; Moquin DM et al. 2013). Caspase-8 (CASP8) in human and rodent cells facilitates the cleavage of kinases RIPK1 and RIPK3 and prevents RIPK1/RIPK3-dependent necroptosis (Lin Y et al. 1999; Hopkins-Donaldson S et al. 2000; Newton K et al. 2019; Zhang X et al. 2019; Lalaoui N et al. 2020). CASP8-mediated cleavage of human RIPK1 after D324 (D325 in mice) separates the amino-terminal kinase domain from the carboxy-terminal part of the molecule preventing RIPK1 kinase activation through dimerization via the carboxy-terminal death domain and leads to the dissociation of the complex TRADD:TRAF2:RIP1:FADD:CASP8 (Lin Y et al. 1999; Meng H et al. 2018). The lack of CASP8 proteolytic activity in the presence of viral (e.g. CrmA and vICA) or pharmacological caspase inhibitors results in necroptosis induction via RIPK1 and RIPK3 (Tewari M & Dixit VM 1995; Fliss PM & Brune W 2012; Hopkins-Donaldson S et al. 2000). Cellular FLICE-like inhibitory protein (cFLIP), which is an NF-κB target gene, form heterodimer with procaspase-8 and inhibits activation of CASP8 within the the TRADD:TRAF2:RIP1:FADD:CASP8:FLIP complex (Yu JW et al. 2009; Pop C et al. 2011). The presence of cFLIP (long form) limits CASP8 to cleave CASP3/7 but allow cleavage of RIPK1 to cause the dissociation of the TRADD:TRAF2:RIP1:FADD:CASP8, thereby inhibiting both apoptosis and necroptosis (Boatright KM et al. 2004; Yu JW et al. 2009; Pop C et al. 2011; Feoktistova M et al. 2011). Mice that lack CASP8 or knock-in mice that express catalytically inactive CASP8 (C362A) die in a RIPK3- and MLKL-dependent manner during embryogenesis (Kaiser WJ et al. 2011; Newton K et al. 2019). Studies using mice that express RIPK1(D325A), in which the CASP8 cleavage site Asp325 had been mutated, further confirmed that cleavage of RIPK1 by CASP8 is a mechanism for dismantling death-inducing complexes for limiting aberrant cell death in response to stimuli (Newton K et al. 2019; Lalaoui N et al. 2020). Disrupted cleavage of RIPK1 variants with mutations at D324 by CASP8 in humans leads to an autoinflammatory response by promoting the activation of RIPK1 (Tao P et al. 2020; Lalaoui N et al. 2020).
Identifier: R-HSA-9686930
Species: Homo sapiens
Compartment: plasma membrane
Caspase-8 (CASP8) in human and rodent cells facilitates the cleavage of receptor-interacting protein kinases RIPK1 and RIPK3 and prevents RIPK1/RIPK3-dependent regulated necrosis (Lin Y et al. 1999; Hopkins-Donaldson S et al. 2000). These cleavage sites are identified to be Asp324 in RIPK1 and Asp328 in RIPK3 in humans (Lin Y et al. 1999; Feng S et al. 2007). The lack of CASP8 proteolytic activity in the presence of viral (e.g. CrmA and vICA) or pharmacological caspase inhibitors results in necroptosis induction via RIPK1 and RIPK3 (Tewari M & Dixit VM 1995; Fliss PM & Brune W 2012; Hopkins-Donaldson S et al. 2000).
Identifier: R-HSA-9687458
Species: Homo sapiens
Compartment: cytosol
During infection in human cells, herpes simplex virus 1 (HSV1) and HSV2 modulate cell death pathways using the large subunit (R1) of viral ribonucleotide reductase (RIR1 or UL39) proteins (Dufour F et al. 2011; Guo H et al. 2015; Yu X et al. 2016; Ali M et al. 2019). The HSV1 and HSV2 RIR1 proteins suppress death receptor-dependent apoptosis by interacting with death effector domains of caspase 8 (CASP8) via a conserved C-terminal ribonucleotide reductase (RNR) domain (Dufour F et al. 2011). The ability of HSV1 RIR1 and HSV2 RIR1 to bind CASP8 is integral to their suppression activity against necroptosis in human cells. Necroptosis complements apoptosis as a host defense pathway to stop virus infection and is mediated by the interaction between receptor‐interacting protein kinase 1 (RIPK1) and RIPK3 that occurs downstream of tumor necrosis factor receptor 1 (TNFR1) activation during the programmed cell death response (Sun X et al. 2002). The N-terminal region of HSV1 and HSV2 RIR1 proteins carrying the RIP homotypic interaction motif (RHIM)-like element is sufficient for RHIM-dependent interaction with RIPK1 and RIPK3 thus inhibiting the interaction between RIPK1 and RIPK3 (Guo H et al. 2015; Yu X et al. 2015). HSV1 RIR1 and HSV2 RIR1 are thought to block the programmed cell death responses in infected human cells by interactions with RIPK1, RIPK3 and CASP8 (Guo H et al. 2015; Mocarski ES et al. 2015).

Pathway (3 results from a total of 3)

Identifier: R-HSA-5218900
Species: Homo sapiens
Cell death triggered by extrinsic stimuli via death receptors or toll-like receptors (e.g., TLR3, TLR4) may result in either apoptosis or regulated necrosis (necroptosis) (Holler N et al. 2000; Kalai M et al. 2002; Kaiser WJ and Offermann MK 2005; Yang P et al. 2007). Caspase-8 (CASP8) is a cysteine protease, which functions as a key mediator for determining which form of cell death will occur (Kalai M et al. 2002). The proteolytic activity of a fully processed, heterotetrameric form of CASP8 in human and rodent cells is required for proapoptotic signaling and also for a cleavage of kinases RIPK1 and RIPK3, while at the same time preventing RIPK1/RIPK3-dependent regulated necrosis (Juo P et al. 1998; Lin Y et al. 1999; Holler N et al. 2000; Hopkins-Donaldson S et al. 2000). A blockage of CASP8 activity in the presence of caspase inhibitors such as Z-VAD-FMK (pan-caspase inhibitor), endogenous FLIP(S) or viral FLIP-like protein was found to switch signaling to necrotic cell death (Thome M et al. 1997; Kalai M et al. 2002; Feoktistova M et al. 2011; Sawai H 2013).
Identifier: R-HSA-3371378
Species: Homo sapiens
c-FLIP proteins (CASP8 and FADD-like apoptosis regulators or c-FLICE inhibitory proteins) are death effector domain (DED)-containing proteins that are recruited to the death-inducing signaling complex (DISC) to regulate activation of caspases-8. Three out of 13 distinct spliced variants of c-FLIP had been found to be expressed at the protein level, the 26 kDa short form FLIP(S), the 24 kDa form FLIP(R), and the 55 kDa long form FLIP(L) (Irmler M et al. 1997; Shu HB et al. 1997; Srinivasula SM et al. 1997; Scaffidi C et al. 1999; Golks A et al. 2005; Haag C et al. 2011)

All c-FLIP proteins carry two DEDs at their N termini, which can bind FADD and procaspase-8. In addition to two DEDs, FLIP(L) contains a large (p20) and a small (p12) caspase-like domain without catalytic activity. FLIP(S) and FLIP(R) consist of two DEDs and a small C terminus. Depending on its level of expression FLIP(L) may function as an anti-apoptotic or pro-apoptotic factor, while FLIP(S) and FLIP(R) protect cells from apoptosis by blocking the processing of caspase-8 at the receptor level (Scaffidi C et al. 1999; Golks A et al. 2005; Toivonen HT et al. 2011; Fricker N et al. 2010).

Identifier: R-HSA-5620971
Species: Homo sapiens
Pyroptosis is a form of lytic inflammatory programmed cell death that is triggered by microbial infection or pathological stimuli, such as stroke or cancer (reviewed in Shi J et al. 2017; Man SM et al. 2017; Tang D et al. 2019; Zheng Z & Li G 2020). The process of pyroptosis protects the host from microbial infection but can also lead to pathological inflammation if overactivated. The morphologic characteristics of pyroptosis include cell swelling, rupture of the cell membrane and release of intracellular contents into the extracellular environment. Pyroptosis is also characterized by chromatin condensation, however this is not the key or universal feature of pyroptosis (reviewed in Man SM et al. 2017; Tang D et al. 2019). Pyroptosis is executed by proteins of the gasdermin family, which mediate formation of membrane pores (Liu X et al. 2016; Ding J et al. 2016; Mulvihill E et al. 2018; Broz P et al. 2020). Pyroptosis can be defined as gasdermin-mediated programmed necrotic cell death (Shi J et al. 2017; Galluzzi L et al. 2018). The gasdermin (GSDM) superfamily includes GSDMA, GSDMB, GSDMC, GSDMD, GSDME (or DFNA5) and PJVK (DFNB59) (Kovacs SB & Miao EA 2018). Each protein contains an N-terminal domain with intrinsic necrotic pore-forming activity and a C‑terminal domain reported to inhibit cell death through intramolecular domain association (Liu X et al. 2016; Ding J et al. 2016; Liu Z et al. 2018, 2019; Kuang S et al. 2017). Proteolytic cleavage in the linker connecting the N‑ and C‑terminal domains of gasdermins releases the C‑terminus, allowing the gasdermin N‑terminus to translocate to the cell membrane and oligomerize to form pores (Shi J et al. 2015; Ding J et al. 2016; Sborgi L et al. 2016; Feng S et al. 2018; Yang J et al. 2018; Mulvihill E et al. 2018). Although PJVK (DFNB59) is included to the gasdermin family, it is not known whether PJVK is cleaved and whether the full length or the N-terminal portion of PJVK is responsible for forming membrane pores. The N‑terminal fragments of GSDMs strongly bind to phosphatidylinositol phosphates and weakly to phosphatidylserine, found on the inner leaflet of the plasma membrane (Liu X et al. 2016; Ding J et al. 2016; Mulvihill E et al. 2018). Gasdermins are also able to target cardiolipin, which is often found in mitochondrial membranes and membranes of bacteria (Liu X et al. 2016; Rogers C et al. 2019). The size of the GSDMD pore is estimated to be 10–20 nm (Ding J et al. 2016; Sborgi L et al. 2016). The pore‑forming activity of GSDMs in the cell membrane facilitates the release of inflammatory molecules such as interleukin (IL)‑1β and IL‑18 (mainly in GSDMD-mediated pyroptosis), and eventually leads to cytolysis in mammalian cells, releasing additional proinflammatory cellular contents including danger signals such as high mobility group box‑1 (HMGB1) (Shi J et al. 2015; He W et al. 2015; Evavold CL et al. 2017; Semino C et al. 2018; Volchuk A et al. 2020). Pyroptosis can occur in immune cells such as macrophages, monocytes and dendritic cells and non‑immune cell types such as intestinal epithelial cells, trophoblasts and hepatocytes (Taabazuing CY et al. 2017; Li H et al. 2019; Jia C et al. 2019). GSDME can be cleaved by caspase‑3 (CASP3) to induce pyroptosis downstream of the “apoptotic” machinery (Wang Y et al. 2017; Rogers C et al. 2017), whereas GSDMD is cleaved by inflammatory CASP1, CASP4 and CASP5 in humans, and CASP1, CASP11 in mice to induce pyroptosis associated with inflammasome activation (Shi J et al. 2015; Kayagaki N et al. 2015). CASP3 cleavage of GSDMD results in its inactivation (Taabazuing et al. 2017). In mouse macrophages, CASP8 can also cleave GSDMD and cause pyroptosis when TAK1 is inhibited (Malireddi R et al. 2018; Orning P et al. 2018; Sarhan J et al. 2018), and TAK1 inhibition also leads to GSDME cleavage (Sarhan J et al. 2018). Furthermore, activated CASP8 can drive inflammasome-independent cleavage of both pro-IL-1β and GSDMD downstream of the extrinsic cell death receptor signaling pathway switching apoptotic signaling to GSDMD-dependent pyroptotic-like cell death (Donado CA et al. 2020). The cleavage and activation of GSDMD in neutrophils is mediated by neutrophil elastase (NE or ELANE), which is released from azurophil granules into the cytosol during neutrophil extracellular trap (NET) formation (Kambara H et al. 2018). Further, granzyme A (GZMA) released from cytotoxic T lymphocytes and natural killer (NK) cells specifically target GSDMB for interdomain cleavage to activate GSDMB-dependent pyroptosis in target tumor cells (Zhou Z et al. 2020). Similarly, granzyme B (GZMB) released from cytotoxic T lymphocytes and natural killer (NK) cells, can induce GSDME‑dependent lytic cell death in tumor targets via the CASP3‑mediated cleavage of GSDME (Zhang Z et al. 2020).

This Reactome module describes pyroptotic activities of GSDMD and GSDME. While the N‑terminal domains of mammalian GSDMA, GSDMB, and GSDMC also have the ability to form pores (Feng S et al. 2018; Ruan J et al. 2018), their functions in the induction of pyroptosis, secretion of proinflammatory cytokines or in bactericidal activity in host remain to be studied and are not covered by this Reactome module.

Complex (3 results from a total of 3)

Identifier: R-HSA-5692539
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9687483
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-3927930
Species: Homo sapiens
Compartment: nucleoplasm

Set (1 results from a total of 1)

Identifier: R-HSA-933463
Species: Homo sapiens
Compartment: cytosol

Icon (1 results from a total of 1)

Species: Homo sapiens
Pro Caspase-8
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