Finally, group III includes the human initiator caspases-8, -9, and -10, which all contain a long pro-domain and prefer substrates with a leucine or valine at the P4 position.
What are the cellular function of caspases?
Caspases are involved in cell death mediated by apoptosis, pyroptosis, necroptosis and autophagy. Caspase function is not limited to cell death. Non-apoptotic roles of caspases include proliferation, tumor suppression, differentiation, neural development and axon guidance and aging.
What is the role of caspases in apoptosis?
Caspases are crucial mediators of apoptosis, a form of physiological cell death. Their activation is carefully controlled by a philogenetically conserved death program, which is indispensable for the homeostasis and development of higher organisms.
What is the role of caspase enzymes?
Caspases, also as cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases, are a family of protease enzymes that provide critical links in cell regulatory networks controlling inflammation and cell death.
What is the primary substrate for caspase-9 during the process of initiating apoptosis?
Figure 6. PARN, ATXN2L, and RING1 are the substrates of both caspase-9 and -3, and they are proteolyzed during STS-induced apoptosis.
What is the role of caspase-3 in apoptosis?
Caspases are crucial mediators of programmed cell death (apoptosis). Among them, caspase-3 is a frequently activated death protease, catalyzing the specific cleavage of many key cellular proteins. However, the specific requirements of this (or any other) caspase in apoptosis have remained largely unknown until now.
What is the role of caspase-8 in apoptosis?
Caspase-8 is a critical molecule as its absence leads to death of mice in utero. Upon activation, its main function is to promote apoptosis and, in thymus, apoptosis of negative selection is critical to eliminate autoaggressive T-cell clones that, if not eliminated, could contribute to develop autoimmune diseases.
What is the function of the caspase-9 when it is active?
Caspase-9 is essential to eliminate cells by executing apoptotic death early in development stage as it is indispensable to inhibit proliferative diseases through the continuous removal of irreparable cells in the lifecycle.
How is caspase activated?
Initiator caspases are activated in three distinct protein complexes, the death-inducing signaling complex (DISC; Caspase-8 and -10), the apoptosome (Caspase-9), and the PIDDosome (Caspase-2). The DISC is formed following ligand binding and death receptor oligomerization.
What proteins are cleaved by caspases?
Caspases. Caspases are a family of cysteine proteases that cleave proteins following aspartic acid residues. These proteases exist in a hierarchy with upstream caspases 2, 8, 9, and 10 and downstream caspases 3, 6, and 7.
What is the function of caspase-3 and 7?
Caspase 3 controls DNA fragmentation and morphologic changes of apoptosis, whereas caspase 7 plays little role in these processes. In contrast, caspase 7 appears to be more important to the loss of cellular viability, although the combined role of both caspases is crucial in this area.
What does caspases mean?
Caspases (cysteine-dependent aspartyl-specific protease) belong to a family of cysteine proteases that mediate proteolytic events indispensable for biological phenomena such as cell death and inflammation. The first caspase was identified as an executioner of apoptotic cell death in the worm Caenorhabditis elegans.
What is the function of the initiator caspase?
The initial signal on the cell membrane or from the mitochondria activates the initiator caspases, which act on execution caspases. These then act on enzymes, nucleic acids, and the cytoskeletal proteins, thus leading to the fragmentation of the nucleus and cytoplasm into membrane-bound apoptotic bodies.
Which of the following triggers the activation of caspase-9?
Caspase-9 is auto-activated when it binds to apaf-1(apoptosome), as apaf-1 oligomerizes the precursor molecules of pro-caspase-9. Previously activated caspases can cleave caspase-9, causing its dimerization.
How is the initiator caspase first activated in response to an apoptotic signal?
After cytochrome c translocates into the cytosol, it interacts with Apaf-1, which undergoes a conformational change and oligomerization into a heptameric structure known as the apoptosome. The apoptosome recruits and activates the initiator caspase, caspase-9.
How does caspase-9 activation caspase-3?
The activation of caspase-3, usually mediated by activated caspase-9, entails a single proteolytic cleavage between the large and small subunits of caspase-3 (5). In contrast, caspase-9 exists as a monomeric, inactive zymogen in cells. The intrachain cleavage is insufficient for the activation of caspase-9 (6–8).
What proteins does caspase-3 cleave?
Once activated, caspase-3 will cleave key structural proteins, cell cycle proteins, and DNase proteins, such as poly(ADP-ribose) polymerase, gelsolin, ICAD/DFF, and DNA-dependent kinase11,12,13. These cleavage events result in the blebbing and condensing of cells that ultimately leads to cell death14.
Is caspase-3 a marker of apoptosis?
This caspase is responsible for the majority of proteolysis during apoptosis, and detection of cleaved caspase-3 is therefore considered a reliable marker for cells that are dying, or have died by apoptosis. This protocol outlines the quantification of apoptosis by flow cytometric detection of cleaved caspase-3.
What is the difference between caspase-3 and cleaved caspase-3?
One specific effector caspase is caspase-3, a protein that is cleaved and thus activated upon the initiation of apoptosis. Cleaved caspase-3 propagates an apoptotic signal through enzymatic activity on downstream targets, including poly ADP ribose polymerase (PARP) and other substrates (2).
How is caspase 7 activated?
Caspase-7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex. J Biol Chem.
What is the meaning of caspase-8?
Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.
Why is caspase so named?
They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue.
Where is caspase-3 activated?
Activation. Caspase-3 is activated in the apoptotic cell both by extrinsic (death ligand) and intrinsic (mitochondrial) pathways. The zymogen feature of caspase-3 is necessary because if unregulated, caspase activity would kill cells indiscriminately.
How does cytochrome c activate caspase-9?
Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem. 2000 Oct 6;275(40):31199-203. doi: 10.1074/jbc.
What is caspase independent apoptosis?
We define caspase-independent cell death (CICD) as death that ensues when a signal that normally induces apoptosis fails to activate caspases. Even so, CICD often shares common characteristics with apoptotic cell death (Table 1).