Search results for CASP8

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Reaction (18 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).
Identifier: R-HSA-9697750
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 NFkB signaling is dependent on autocrine/paracrine signals, on the cellular context and tightly regulated by posttranslational modifications of RIP1 itself. Following ligation of TNFR1, RIPK1 is recruited to the TNFR1:TRADD:TRAF2 complex where it is ubiquitinated by BIRC2/3 (also known as inhibitor of apoptosis proteins cIAP1/2) and LUBAC. Polyubiquitination of RIPK1 is required for recruitment of signaling molecules/complexes such as the IKK complex and TAK1 complex. IKKs and TAK1 phosphorylate RIPK1 to limit its cytotoxic activity and activate NFkappaB and MAPK pathways, resulting in expression of both pro-inflammatory cytokines and pro-survival genes including FADD-like interleukin-1 beta converting enzyme (FLICE)-inhibitory protein (cFLIP, encoded by the CFLAR gene) (Ea CK et al. 2006). Conversely, deubiquitination of RIPK1, mediated by BIRC2/3 (cIAP) inhibition or the deubiquitylases A20 or CYLD, switches the pro-survival function of RIPK1 to caspase-mediated pro-apoptotic signaling (Fujikura D et al. 2012; Moquin DM et al. 2013). The TRADD:TRAF2:RIPK1 complex detaches from TNFR1 and recruits FADD and procaspase-8 (CASP8). 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; Meng H et al. 2018; Newton K et al. 2019; Zhang X et al. 2019; Tao P et al. 2020; Lalaoui N et al. 2020). The balance between caspase-dependent apoptosis and RIPK-dependent necroptosis was found to depend on the levels of CASP8 and cFLIP (CFLAR) (reviewed in Tummers B & Green DR 2017). In the presence of cFLIP, both CASP8 and FLIP are recruited to the TRADD:TRAF2:RIPK1:FADD complex. cFLIP exists in two main isoforms: long FLIP(L) and short FLIP(S) forms. The heterodimers of FLIP(L):CASP8 inhibit CASP8 activity limiting the cleavage of CASP3/7 but allowing the cleavage of RIPK1 to cause the dissociation of the TRADD:TRAF2:RIPK1:FADD:CASP8 complex, thereby inhibiting both apoptosis and necroptosis (Pop C et al. 2011; Oberst A et al. 2011; Hughes MA et al. 2009; Lalaoui N et al 2020). FLIP(S) has also been proposed to induce necroptosis in conditions when RIPK1 is deubiquitylated and when FLIP(L) is absent (Feoktistova M et al. 2011). Note that the latest statement has been proven in the context of the TLR3 signalling pathway.
Identifier: R-HSA-5228521
Species: Homo sapiens
Compartment: nucleoplasm
PIAS1, PIAS4 SUMOylate CASP8AP2 (FLASH) at lysine-1813 with SUMO1 (Alm-Kristiansen et al. 2009, Alm-Kristiansen et al. 2011). SUMOylation enhances the transcriptional coactivation activity of CASP8AP2. As inferred from mouse homologs, SUMOylation also appears to trigger proteasomal degradation of CASP8AP2 (Vennemann and Hofmann 2013).
Identifier: R-HSA-3927824
Species: Homo sapiens
Compartment: nucleoplasm
The CBX3 component of PRC1 SUMOylates CASP8AP2 (FLASH) at lysine-1813 with SUMO1 (Alm-Kristiansen et al. 2009). SUMOylation enhances the transcriptional coactivation activity of CASP8AP2. SUMOylation also appears to trigger proteasomal degradation of CASP8AP2 (Vennemann and Hofmann 2013).
Identifier: R-HSA-6800035
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
IGFBP3 binds a cell death receptor TMEM219 (IGFBP-3R), a single-span transmembrane protein. Activated TMEM219 can trigger apoptosis, probably by directly binding to and activating caspase-8 (CASP8) (Ingermann et al. 2010).
Identifier: R-HSA-5675456
Species: Homo sapiens
Compartment: cytosol, plasma membrane
The balance between caspase-dependent apoptosis and RIPK-dependent necroptosis was found to depend on the levels of caspase-8 (CASP8) and cellular FADD-like interleukin-1 beta converting enzyme (FLICE)-inhibitory protein (cFLIP, encoded by the CFLAR gene) (Feoktistova M et al. 2011; Hughes MA et al. 2016; reviewed in Tummers B & Green DR 2017). cFLIP exists in two main isoforms: long FLIP(L) and short FLIP(S) forms. Both FLIP(L) and FLIP(S) form heterodimers with procaspase-8, however they differentially regulate CASP8 activation (Feoktistova M et al. 2011; Dillon CP et al. 2012). The pseudoprotease FLIP(L) interacts with procaspase-8 through both death effector domains (DED) and caspase-like domain (CLD) that lacks catalytic activity due to absence of a cysteine residue in FLIP(L). The procaspase-8 catalytic domain prefers heterodimerization with the CLD of FLIP(L) over homodimerization with catalytic domains of other procaspase-8 molecules (Boatright KM et al. 2004; Yu JW et al. 2009). Heterodimerization to FLIP(L) rearranges the catalytic site of procaspase-8, producing a conformation that renders the heterodimer highly active even in the absence of proteolytic processing of either caspase-8 or cFLIPL (Micheau O et al. 2002; Yu JW et al. 2009; reviewed in Tummers B & Green DR 2017). The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011; Hughes MA et al. 2016). When FLIP(L) is expressed at high levels, the enzymatic activity of the FLIP(L):CASP8 heterodimer with procaspase-8 being an active unit is insufficient to generate active CASP8 heterotetramers for the apoptosis induction in mammalian cells. In contrary, the residual catalytic activity of FLIP(L):CASP8 is sufficient for RIPK1/RIPK3 cleavage, which inhibited the necroptotic cell death mode (Feoktistova M et al. 2011; Dillon CP et al. 2012; Oberst A et al. 2011).
Identifier: R-HSA-9697747
Species: Homo sapiens
Compartment: cytosol
The balance between caspase-dependent apoptosis and RIPK-dependent necroptosis was found to depend on the levels of FADD-like interleukin-1 beta converting enzyme (FLICE)-inhibitory protein isoforms (cFLIP, encoded by the CFLAR gene) (reviewed in Tummers B & Green DR 2017). cFLIP exists in two main isoforms: long FLIP(L) and short FLIP(S) forms. Both FLIP(L) and FLIP(S) dimerize with procaspase-8 at the death‑inducing signaling complex (DISC) such as TRADD:TRAF2:RIPK1: FADD:CASP8:FLIP(L), however they differentially regulate CASP8 activation (Pop C et al. 2011; Oberst A et al. 2011; Hughes MA et al. 2009, 2016). The heterodimers of FLIP(L):CASP8 inhibit CASP8 activity limiting the cleavage of CASP3/7 but allowing the cleavage of RIPK1 to cause the dissociation of the TRADD:TRAF2:RIPK1:FADD:CASP8 complex, thereby inhibiting both apoptosis and necroptosis (Pop C et al. 2011; Oberst A et al. 2011; Hughes MA et al. 2009; Lalaoui N et al 2020). Processing of FLIP(L) also occurs at the DISC and depends on CASP8 activity (zymogen and mature form). Upon activation FLIP(L) is cleaved to generate N‑terminal FLIP(p43) and C‑terminal FLIP(p12) (Irmler M et al. 1997; Chang DW et al. 2002; Yu JW et al. 2009; Pop C et al. 2011). FLIP(S) is a truncated version of procaspase‑8 containing tandem DEDs only. FLIP(S) acts purely as an antagonist of CASP8 activity inhibiting apoptosis. FLIP(S) has also been proposed to induce necroptosis in conditions when RIPK1 is deubiquitylated and when FLIP(L) is absent (Feoktistova M et al. 2011). Important to note that the latest statement has been shown in the context of the TLR3 signalling pathway.
Identifier: R-HSA-9603534
Species: Homo sapiens
Compartment: plasma membrane, cytosol
In the absence of ligand, NTRK3 (TRKC) is cleaved by an unknown caspase. CASP3 (caspase-3) cleaves NTRK3 in vitro, but CASP3 inhibitors do not prevent NTRK3 cleavage in live cells. CASP8 (caspase-8) is unable to cleave NTRK3 in vitro. A general caspase inhibitor prevents NTRK3 cleavage in live cells (Tauszig-Delamasure et al. 2007).
Identifier: R-HSA-5692550
Species: Homo sapiens
Compartment: cytosol
Human cytomegalovirus (HCMV) encodes several viral cell death inhibitors that target different key regulators of the extrinsic and intrinsic apoptotic pathways. Viral inhibitor of caspase-8 activation (vICA) protein encoded by the UL36 gene suppresses the extrinsic apoptotic signaling pathway by binding to the prodomain of caspase-8 (CASP8) and preventing its activation (Skaletskaya A et al. 2001; McCormick et al, 2010; Fliss PM & Brune W 2012).
Identifier: R-HSA-9687465
Species: Homo sapiens
Compartment: cytosol
Necroptosis complements apoptosis as a host defense pathway to stop virus infection. During infection in human cells, herpes simplex virus (HSV)-1 and HSV-2 modulate cell death pathways using the large subunit (R1) of viral ribonucleotide reductase (RIR1 or UL39) (Dufour F et al. 2011; Guo H et al. 2015; Yu X et al. 2016; Ali M et al.2019). The N-terminal region of RIR1 protein carrying the RIP homotypic interaction motif (RHIM)-like element is sufficient for RHIM-dependent interaction with receptor‐interacting protein kinase 1 (RIPK1) and receptor‐interacting protein kinase 3 (RIPK3) thus inhibiting the interaction between RIPK1 and RIPK3 (Guo H et al. 2015; Yu X et al. 2015). An intact RHIM is required for the interaction between RIPK1 and RIPK3 that occurs downstream of tumour necrosis factor receptor 1 (TNFR1) activation during the programmed cell death response known as necroptosis (Sun X et al. 2002). In addition, the large carboxyl-terminal region of HSV RIR1 protein mediates the binding to caspase 8 (CASP8) (Dufour F et al. 2011; Guo H et al. 2015). HSV RIR1 is thought to block necroptosis in infected human cells by interactions with RIPK1, RIPK3 and CASP8 (Guo H et al. 2015; Mocarski ES et al. 2015).
Identifier: R-HSA-9687455
Species: Homo sapiens
Compartment: cytosol
During infection in human cells, herpes simplex virus (HSV)-1 and HSV-2 modulate cell death pathways using the large subunit (R1) of viral ribonucleotide reductase (RIR1 or UL39) (Dufour F et al. 2011; Guo H et al. 2015; Yu X et al. 2016; Ali M et al.2019). The N-terminal region of RIR1 protein carrying the RIP homotypic interaction motif (RHIM)-like element is sufficient for RHIM-dependent interaction with receptor‐interacting protein kinase 1 (RIPK1) and receptor‐interacting protein kinase 3 (RIPK3) thus inhibiting the interaction between RIPK1 and RIPK3 (Guo H et al. 2015; Yu X et al. 2015). An intact RHIM is required for the interaction between RIPK1 and RIPK3 that occurs downstream of tumour necrosis factor receptor 1 (TNFR1) activation during the programmed cell death response known as necroptosis (Sun X et al. 2002). In addition, the large carboxyl-terminal region of HSV RIR1 protein mediates the binding to caspase 8 (CASP8) (Dufour F et al. 2011; Guo H et al. 2015). HSV RIR1 is thought to block necroptosis in infected human cells by interactions with RIPK1, RIPK3 and CASP8 (Guo H et al. 2015; Mocarski ES et al. 2015).
Identifier: R-HSA-3465429
Species: Homo sapiens
Compartment: cytosol, plasma membrane
The short form of cellular FLIP (FLIP(S) or c-FLIPS) has two death effector domains DEDs, which can bind to FADD and caspase-8 (CASP8). FLIP(S) protects the cells from apoptosis by inhibiting the processing of caspase-8 at the receptor level (Scaffidi C et al. 1999; Micheau O et al 2001).

FLIP(S) is a short-lived protein which is sensitive to ubiquitination and proteasomal degradation (Poukkula M et al. 2005). Protein kinase C (PKC)- mediated phosphorylation of FLIP(S) at Ser193 was shown to prolongs the half-life of FLIP(S) by inhibiting its polyubiquitination (Kaunisto A et al. 2009).

Identifier: R-HSA-933526
Species: Homo sapiens
Compartment: cytosol, mitochondrial outer membrane
Caspase-8 (CASP8) and caspase-10 (CASP10) are involved in RIG-I/MDA5-dependent antiviral immune responses. Caspase-8/10 activation contributes to NF-kB activation in response to viral dsRNA.
Caspase-8/10 are synthesized as zymogens (procaspases), containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domain separated by a smaller linker region. FADD plays a crucial role in the recruitment and activation of procaspase-8/10. The two DED domains of procaspase-8/10 interacts with DED domain of FADD.
Identifier: R-HSA-622420
Species: Homo sapiens
Compartment: cytosol
NOD1 was found to coimmunoprecipitate with several procaspases containing long prodomains with CARDs or DEDs, including caspase-1, caspase-2, caspase-4, caspase-8, and caspase-9, but not those with short prodomains like caspase-3 or caspase-7. Deletions of caspase-9 determined that the CARD domain was required for this interaction (Inohara et al. 1999). More recently, NOD1 activation of apoptosis was shown to require the RIP2-dependent activation of caspase-8, this effect being inhibited by CASP8 and FADD-like apoptosis regulator, also called FLICE-inhibitory protein, FLIP or CLARP (da Silva Correia et al. 2007), which is a specific inhibitor of caspase-8 (Irmler et al. 1997).
Identifier: R-HSA-5213462
Species: Homo sapiens
Compartment: cytosol
Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL). The initiation of necroptosis can be stimulated by the same death ligands that activate apoptosis, such as tumor necrosis factor (TNF) alpha, Fas ligand (FasL), and TRAIL (TNF-related apoptosis-inducing ligand) or ligands for toll like receptors 3 (TLR3) and TLR4 (Holler N et al. 2000; He S et al. 2009; Feoktistova M et al. 2011; Voigt S et al. 2014). In contrast to apoptosis, however, necroptosis is optimally induced when caspases are inhibited (Holler N et al. 2000; Sawai H 2014). Otherwise active caspase 8 (CASP8) blocks necroptosis by the proteolytic cleavage of RIPK1 and RIPK3 (Kalai M et al. 2002; Degterev A et al. 2008; Feng S et al. 2007). When CASP8 activity is inhibited under certain pathophysiological conditions or by pharmacological agents, RIPK1 is engaged in physical and functional interactions with its homolog RIPK3 leading to formation of the necrosome, a cytosolic necroptosis-inducing complex consisting of RIPK1 and RIPK3 (Sawai H 2013; Moquin DM et al. 2013; Kalai M et al. 2002; He S et al. 2009, Zhang DW et al. 2009). RIPK3 was found to be essential for necroptosis (He S et al. 2009; Cho YC et al. 2009; Zhang DW et al. 2009). Embryonic fibroblasts from RIPK3 knockout mice were resistant to necrosis induced by TNF or during virus infection (He S et al. 2009; Cho YC et al. 2009). RIPK3-/- mice exhibited severely impaired vaccinia virus (VV)-induced tissue necrosis, inflammation, and control of viral replication (Cho YC et al. 2009). RIPK3 knockout animals were devoid of inflammation inflicted tissue damage in an acute pancreatitis model (He S et al. 2009). Further, RIPK3 knockdown in the human colorectal adenocarcinoma (HT-29) cell line, that stably expressed a shRNA targeting RIPK3, led to blockage of TNF-alpha, TRAIL or FAS-induced pronecrotic signaling pathway (He S et al. 2009). Knockdown of RIPK3 in human keratinocyte HaCaT cells blocked TLR3-mediated necroptosis without affecting the apoptotic response. Moreover, overexpression of RIPK3 in human epithelial carcinoma (HeLa) cells led to increased caspase-independent TLR3-induced cell death in the absence of inhibitors of apoptosis (IAPs) (Feoktistova M et al. 2011). Within the necrosome RIPK1 and RIPK3 bind to each other through their RIP homotypic interaction motif (RHIM) domains (Sun X et al. 2002; Li J et al. 2012; Mompean M et al. 2018). The RHIMs can facilitate RIPK1:RIPK3 oligomerization, allowing them to form amyloid-like fibrillar structures (Li J et al. 2012; Mompean M et al. 2018). RIPK1 serves as a scaffold to enable RIPK3 to assemble into homooligomers. Owing to the size and the toxicity arising from overexpressing RIPK1 and RIPK3 in cells, this has been problematic to study in detail. The underlying mechanism is still debated, but RIPK3 transphosphorylation is believed to be crucial for MLKL activation (Orozco S et al. 2014; Cook WD et al. 2014). Necroptosis is a tightly regulated process. The balance between caspase-dependent apoptosis and RIPK-dependent necroptosis was found to depend on the levels of CASP8 and cellular FADD-like interleukin-1 beta converting enzyme (FLICE)-inhibitory protein (cFLIP, encoded by the CFLAR gene) (Feoktistova M et al. 2011). cFLIP exists in two main isoforms: long cFLIP(L) and short cFLIP(S) forms. cFLIP(L) (CFLAR) prevented apoptosis and necroptosis, whereas FLIP(S) inhibited apoptosis but promoted necroptosis (Feoktistova M et al. 2011; Dillon CP et al. 2012). A blockage of CASP8 activity in the presence of viral FLIP-like protein was found to switch signaling to necrotic cell death (Sawai H 2013). Cell level of free active RIPK1 can be controlled by targeting RIPK1 for proteasomal degradation via K48-linked polyubiquitination mediated by baculoviral IAP repeat containing proteins BIRC2 and BIRC3 (also known as cellular inhibitor of apoptosis proteins cIAP1 and cIAP2) (Varfolomeev E et al, 2008; Bertrand MJM et al. 2008; Tenev T et al. 2011). The carboxyl terminus of Hsp70-interacting protein (CHIP or STUB1) was shown to negatively regulate necroptosis by ubiquitylation-mediated degradation of RIPK3 (Seo J et al. 2016). Further, O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) was found to prevent necroptosis by suppressing RIPK3 activity (Li X et al. 2019; Zhang B et al. 2019). During infection in human cells, herpes simplex virus (HSV)-1 and HSV-2 can modulate cell death pathways using the large subunit (R1) of viral ribonucleotide reductase (RIR1 or UL39). Viral RIR1 blocked necroptosis in infected human cells by interactions with RIPK1, RIPK3 and CASP8 (Guo H et al. 2015; Mocarski ES et al. 2015).

This Reactome event shows RHIM-dependent interaction of RIPK1 and RIPK3.

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