Search results for CYCS

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Reaction (5 results from a total of 11)

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).

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