Search results for CYCS

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Reaction (11 results from a total of 11)

Identifier: R-HSA-1592231
Species: Homo sapiens
Compartment: nucleoplasm, cytosol
The gene encoding cytochrome c (CYCS) is transcribed in the nucleus to yield mRNA and the mRNA is translated in the cytosol to yield the precursor of cytochrome c, which is then imported into the mitochodrial matrix and associates with the matrix face of the inner membrane.
As inferred from rat, PGC-1beta activates expression of cytochrome c (CYCS) (Lin et al. 2003).
ERR1 (ERRalpha) probably interacts with coactivator PGC-1beta to activate expression of cytochrome c (CYCS) (Shao et al. 2010).
Identifier: R-HSA-114254
Species: Homo sapiens
Compartment: cytosol
The apoptotic protease‑activating factor 1 (APAF1) is a cytosolic multidomain adapter protein containing an N‑terminal caspase recruitment domain (CARD), followed by a central nucleotide‑binding & oligomerization domain (NOD, also known as NB‑ARC) and a C‑terminal regulatory region with WD40 repeats which form the 7- and 8-bladed β-propellers (Inohara N and Nunez G 2003; Danot O et al. 2009; Yuan S et al. 2011). Under steady‑state, non‑apoptotic conditions, APAF1 exists as an ADP‑bound, autoinhibited monomer (Riedl SJ et al. 2005; Reubold TF et al. 2009). During apoptosis, cytochrome c (CYCS) is released from the mitochondrial intermembrane space to the cytosol where it binds APAF1 between the two WD40 repeat domains in the C‑terminal regulatory region (Zou et al. 1997; Liu X et al. 1996; Shalaeva DN et al. 2015; Zhou M et al. 2015). CYCS binding causes an upward rotation of the β-propeller region which is accompanied by conformational changes in APAF1 and the replacement of ADP by dATP or ATP triggering APAF1 oligomerization into a heptameric, wheel‑shaped signaling platform (Acehan D et al. 2002; Yu X et al. 2005, Kim HE et al. 2005; Yuan S et al. 2010, 2013; Li P et al. 1997; Jiang X & Wang X 2000; Zhou M et al. 2015). Moreover, the N-terminal CARD in the inactive APAF1 monomer is not shielded from other proteins by β–propellers. Hence, the APAF1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly (Yuan S et al. 2013). Physiological concentrations of calcium ion negatively affect the assembly of apoptosome and activation of CASP9 by inhibiting nucleotide exchange in the monomeric, autoinhibited APAF1 (Bao Q et al. 2007).
Identifier: R-HSA-2466370
Species: Homo sapiens
Compartment: nucleoplasm
As inferred from mouse, PGC-1beta (PPARGC1B) binds NRF1 and coactivates genes regulated by NRF1.
Identifier: R-HSA-6804596
Species: Homo sapiens
Compartment: cytosol
The APAF1 interacting protein (APIP) is an endogenous regulators of the apoptosome apparatus. APIP is thought to bind to the CARD domain of APAF1 preventing procaspase-9 recruitment to the apoptosome (Cho DH et al., 2004; Cao G et al., 2004; Kang W et al. 2014). Moreover, during hypoxic conditions, APIP may also induce sustained activation of AKT and ERK1/2 kinases, which directly phosphorylate procaspase-9 to inhibit its activation in the apoptosome (Cho DH et al., 2007).
Identifier: R-HSA-114256
Species: Homo sapiens
Compartment: cytosol
The protease caspase‑9 (CASP9) is normally present as an inactive monomeric propeptide (procaspase‑9 or zymogen). Upon apoptosis procaspase‑9 (CASP9(1‑416) is recruited to APAF1:cytochrome C (CYCS):ATP complex to form the caspase‑activating apoptosome (Hu Q et al. 2014; Cheng TC et al. 2016). The cryo-EM structures have established that the nucleotide-binding oligomerization domain (NOD) of APAF1 mediates the heptameric oligomerization of APAF1, while its tryptophan-aspartic acid (WD40) domain interacts with CYCS (Yuan S & Akey CW 2013). The caspase recruitment domain (CARD) of APAF1 recruits the N‑terminal CARD of CASP9(1‑416) through homotypic CARD:CARD interactions (Li P et al. 1997; Qin H et al. 1999; Yuan S et al. 2010; Yuan S & Akey CW 2013). These homotypic interaction motifs are thought to interact with each other through three types of interfaces, type I, II, and III, which cooperate to generate homo- and hetero-oligomers from relatively small assemblies to open-ended filaments (Ferrao R & Wu H 2012). Structural and mutagenesis studies showed that all type I, II, and III interfaces are involved in the caspase-9 activation by APAF1-mediated helical oligomerization of CARDs (Hu Q et al. 2014; Cheng TC et al. 2016; Su TW et al. 2017; Li Y et al. 2017). Cryo-EM structure of the holo-apoptosome revealed an oligomeric CARD disk above the heptameric apoptosome ring with estimated molecular ratios between 2-5 zymogens per 7 APAF1 molecules (Hu Q et al. 2014; Cheng TC et al. 2016). The structural and biochemical studies showed that APAF1-CARD and CASP9-CARD initially formed a 1:1 complex in solution, which at higher concentrations is further oligomerized into a 3:3 complex. The 3:3 complex was reported as a core arrangement of the 4:3 or 4:4 APAF1-CARD:CASP9-CARD complex in the helical assembly of the CARD disk (Cheng TC et al. 2016; Su TW et al. 2017; Li Y et al. 2017; Dorstyn L et al. 2018). Thus, APAF1:CASP9 (1-416) heterodimers may be recruted to the assembling apoptosome as part of its activation.

The Reactome event describes the apoptosome assembly with the stoichiometry of 4 procaspase-9 zymogens per 7 APAF1 molecules. The formation of 1:1 and other combinations of APAF1:CASP9(1-416) complexes is not shown.

Identifier: R-HSA-9710354
Species: Homo sapiens
Compartment: cytosol, mitochondrial outer membrane
Gasdermin E (GSDME) is cleaved by caspase 3 (CASP3) at D270 in response to apoptotic stimuli (Rogers C et al. 2017; Wang Y et al. 2017). The released N‑terminal fragment of GSDME (1‑270) targets the plasma membrane to drive pyroptosis in GSDME‑expressing cells (Wang Y et al. 2017). In addition, the N‑terminal fragment of mouse GSDME binds to cardiolipin liposomes causing severe leakage (Wang Y et al. 2017). Although cardiolipin is primarily located in the inner mitochondrial membrane, the outer mitochondrial membrane also contains around 10‑20% cardiolipin and cardiolipin translocates in a regulatable manner between the compartments (Liu J et al. 2003; reviewed in Dudek J 2017). Confocal microscopy and biochemical analysis revealed that tagged‑GSDME (1‑270) localized to mitochondria and triggered release of proapoptotic proteins such as cytochrome c (CYCS) upon ectopic expression in human HeLa cells or human embryonic kidney 293T (HEK293T) cells (Rogers C et al. 2019). Endogenous GSDME (1‑270) also localized to the mitochondrial fraction during apoptosis in TNFα plus actinomycin D (TNFα/actD)‑treated human lymphoid CEM‑C7 cells. Apoptotic stimuli‑triggered cleavage of GSDME (1‑270) induced CYCS release and ROS production in CEM‑C7 cells (Rogers C et al. 2019). These data suggest that the N‑terminal fragment of GSDME (1‑270) can permeabilize the mitochondria in response to apoptotic stimuli (Rogers C et al. 2019), however, the physiological relevance of this event remains to be determined.

This Reactome event describes the GSDME (1‑275) binding to mitochondrial cardiolipin leading to CYCS release from the mitochondria.

Identifier: R-HSA-9710353
Species: Homo sapiens
Compartment: cytosol, mitochondrial outer membrane
Gasdermin D (GSDMD) is cleaved by inflammatory caspases (CASP) downstream of inflammasome activation (Shi J et al. 2015). The released N‑terminal fragment of GSDMD (1‑275) targets the plasma membrane to drive pyroptosis. In addition, GSDMD (1‑275) can bind to and permeabilize liposomes containing cardiolipin, a phospholipid found on the mitochondrial membrane and bacterial membranes (Ding J et al. 2016; Liu X et al. 2016). Although cardiolipin is primarily located in the inner mitochondrial membrane, the outer mitochondrial membrane also contains around 10‑20% cardiolipin and cardiolipin has been shown to translocate in a regulatable manner between the compartments (Liu et al. 2003; reviewed in Dudek J 2017). Further, upon expression in human embryonic kidney 293T (HEK293T) cells, GSDMD (1‑275) induces cytochrome c (CYCS) release from the mitochondria leading to the CASP3 activation (Rogers C et al. 2019). In a mouse model of inflammatory lung injury, lipopolysaccharide (LPS) triggered caspase‑11‑mediated cleavage of mouse GSDMD, which formed pores on the mitochondrial membrane and induced mitochondrial DNA (mtDNA) release into the cytosol of endothelial cells (Huang LS et al. 2020). Moreover, single‑cell analysis of pyroptosis dynamics in mouse macrophages revealed that GSDMD disrupts the mitochondrial membrane potential and leads to mitochondrial decay that precedes pyroptotic cell lysis (de Vasconcelos NM et al. 2019). These data suggest that the N‑terminal fragment of GSDMD binds mitochondrial cardiolipin and forms pores triggering the release of mitochondrial proteins and DNA, however, the physiological relevance of this event remains to be determined.

This Reactome event describes the GSDMD (1‑275) binding to mitochondrial cardiolipin leading to CYCS release.

Identifier: R-HSA-114259
Species: Homo sapiens
Compartment: cytosol
Procaspase‑9 is processed in an ATP‑dependent manner following association with APAF1 and cytochrome c (CYCS) within the apoptosome complex (Li P et al. 1997). However, caspase‑9 (CASP9) has an unusually active zymogen that does not require proteolytic processing (Stennicke HR et al. 1999). Though dispensable for catalytic activity, CASP9 processing was suggested to serve as a "molecular timer" that can limit the proteolytic activity of this complex through displacement of bound caspase‑9 molecules (Malladi S et al. 2009). In addition, this cleavage exposes a neo‑epitope comprising the NH2‑terminal four amino acids (ATPF) of the small p12 subunit of CASP9 that has been shown to be both necessary and sufficient for binding to the baculovirus IAP repeat 3 (BIR3) domain of XIAP, leading to inhibition of CASP9 activity (Srinivasula SM et al. 2001; Shiozaki EN et al. 2003).
Identifier: R-HSA-9627056
Species: Homo sapiens
Compartment: cytosol
CASP9 is normally present as an inactive monomeric propeptide (procaspase‑9 or zymogen). Upon apoptosis, the N‑terminal caspase recruitment domain (CARD) of procaspase‑9 binds to the exposed CARD of the apoptotic protease‑activating factor‑1 (APAF1) through homotypic interactions (Qin H et al. 1999). Procaspase-9 has been estimated to bind to the apoptosome with ratios between 2–5 zymogens per 7 APAF:cytochrome c (CYCS) molecules (Cheng TC et al. 2016). The function of the apoptosome is to promote homodimerization of CASP9 (Jiang X and Wang X 2000; Srinivasula SM et al. 2001; Shiozaki EN et al. 2002). While activation of CASP9 involves dimerization, proteolytic cleavage of CASP9 may not be required. The unprocessed CASP9 exhibited high catalytic activity (Renatus et al. 2001; Acehan D et al. 2002). Furthermore, unlike other initiator caspases, including caspases‑2, ‑8 and ‑10, the prodomain of CASP9 is not removed during apoptosis; in fact, CASP9 (in both its procaspase‑9 and processed forms) must remain bound to the apoptosome to retain substantial catalytic activity (Bratton et al. 2001; Rodriguez and Lazebnik 1999). Once activated in the apoptosome, CASP9 dimer cleaves and activates procaspase‑3 and ‑7.
Identifier: R-HSA-6805811
Species: Homo sapiens
Compartment: cytosol, mitochondrial outer membrane
Septin 4 gene (SEPT4) encodes several protein isoforms including SEPT4_i2 (also known as apoptosis-related protein in the TGF-beta signaling pathway (ARTS)) (Larisch S et al. 2000).

ARTS (SEPT4_i2) is a mitochondrial pro-apoptotic tumor suppressor protein (Larisch S et al. 2000; Elhasid et al. 2004; Gottfried Y et al. 2004; Lotan R et al. 2005). Following induction of apoptosis, ARTS rapidly translocates to the cytosol where it binds and inhibits X-linked inhibitor of apoptosis protein (XIAP). ARTS is thought to induce apoptosis by promoting the proteasome-mediated degradation of XIAP and blocking its ability to inhibit caspases (Gottfried Y et al. 2004; Bornstein B et al. 2011; Garrison JB et al. 2011; Reingewertz TH et al. 2011). The release of ARTS from mitochondria and its accumulation in the cytosol appears to be a caspase-independent event (Gottfried Y et al. 2004). The protein level of ARTS is tightly regulated through ubiquitin mediated degradation (Lotan R et al. 2005). The translocation of ARTS (SEPT4) from mitochondria precedes the release of both cytochrome c (CYCS) and SMAC (DIABLO) and leads to degradation of XIAP before the release of SMAC (Edison N et al. 2012).

Identifier: R-HSA-6805426
Species: Homo sapiens
Compartment: cytosol
Caspase activating and recruitment domain 8 protein (CARD8, also known as TUCAN, CARDINAL) has been implicated as a regulator of several pro-inflammatory and apoptotic signaling pathways. The C-terminal CARD domain of CARD8 (TUCAN) binds procaspase-9 (CASP9(1-416)) and interferes with binding of APAF1 to procaspase-9 thus suppressing caspase activation induced by the APAF1:cytochrome c (CYCS) axis (Pathan N et al. 2001). The structural studies of CARD8 suggest that in addition to intermolecular CARD-CARD interactions, CARD domain may intramolecularly associate with the N-terminal function to find domain (FIIND) to regulate apoptotic and inflammatory signaling pathways (Jin T et al. 2013).

Several binding partners of CARD8 have been reported. CARD8 can interact physically via CARD domain with caspase-1 and negatively regulates caspase-1-dependent IL-1beta generation in the THP-1 monocytic cell line (Razmara M et al. 2002). The FIIND domain of CARD8 may inhibit NFkappaB activation, possibly through interaction with IKKgamma (Bouchier-Hayes L et al. 2001). FIIND may also bind the nucleotide-binding domain (NBD) domain of NOD2 and NLRP3 to regulate the immune response to bacterial infections (Kampen O et al. 2010).

High levels of CARD8 expression have been observed in several tumor cell lines and malignant specimens from human patients underlying its importance in regulating inflammatory and apoptotic pathways (Bouchier-Hayes L et al. 2001; Pathan N et al. 2001; Razmara M et al. 2002; Zhang H & Fu W 2002; Yamamoto M et al. 2005).

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