What is the difference between initiator and executioner caspases

Caspase-8 goes on to cleave the executioner caspases 3, 6, 7 , which will cleave substrates like Lamin and Rb to result in DNA fragmentation and apoptosis. Growth factor stimulation normally suppresses the intrinsic caspase pathway through PI3K signaling, but loss of this stimulus or the presence of other cellular stresses can activate the intrinsic caspase cascade.

This involves a number of mitochondria-associated factors like BID and cytochrome C, and eventually results in the dimerization of caspase-9 and the subsequent activation of the executioner caspases. Caspase Cascade Caspases are a group of signaling proteins that have proteolytic function, and drive apoptosis through a chain of cleavage events.

The tick salivary gland rapidly degenerates and disappears within 4 days after engorgement [ 53 , 63 ]. Nevertheless, the dsRNAs for RhCaspases 7, 8 and 9 did not completely reduce the degeneration of tick salivary glands. This was expected, since there is redundancy in apoptosis pathways and other types of programmed cell death. Only the simultaneous inhibition of both apoptotic and autophagic pathways impedes salivary gland histolysis [ 64 ]. Co-transfection of the cells with plasmids containing caspase genes was used to study the interaction between the different RhCaspases.

Although co-transfection is a standard method used to analyze protein-protein interaction events in vitro [ 65 ], there are relatively few reports of this type of study in ticks. RhCaspase 7 is an executioner caspase, and RhCaspase 8 and 9 are initiator caspases [ 62 , 66 , 67 ]. Three tick caspase molecules were identified in ticks and the roles of these caspases in tick physiology were studied. Our findings provide a basis for advanced studies on tick apoptosis.

The knockdown of RhCaspase 9 in vivo inhibited blood-feeding of the tick, demonstrating that RhCaspase9 has the potential to become a candidate vaccine molecule. The datasets supporting the conclusions of this article are included within the article and its additional files. Targeting the tick-pathogen interface for novel control strategies.

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First, initiator caspases caspases 8, 9, 10 are activated either by external death ligands triggering the formation of the death-inducing signaling complex DISC; caspases 8 and 10 or by the release of cytochrome c from mitochondria provoking the assembly of the apoptosome caspase The third step is the caspasemediated activation of the executioner caspase-6, a peptidase with a substrate preference similar to that of initiator caspases.

In this manner, the cell amplifies the proteolytic activity of caspases to swiftly cause cell demise. As caspases become active, proteolysis of various death substrates happens with the general goal of stopping crucial cellular processes, but for a limited number of proteins a gain in function occurs, often via the loss of a regulatory domain or the separation of domains carrying different functions. These substrates are difficult to identify as they necessarily require the study of individual fragments generated by caspases and because their proteolysis does not occur in isolation.

Earlier studies have established that most caspases recognize a five-amino-acid motif in their substrates and cleave following an aspartate residue. However, recent reports have muddied the water in respect to these simple rules for substrate recognition and cleavage, 3 , 4 by showing that caspases can also cut after a glutamate residue 5 and employ exosites to improve catalysis. In a recent publication, 7 we identified two novel caspase substrates, sorting nexin SNX 1 and 2, involved in endosomal sorting Figure 1.

The two proteins are cleaved by initiator caspases in vitro and in cellulo during apoptosis. We further showed that SNX1 contains multiple cleavage sites, including following glutamate residues. Interestingly, cellular repression of caspase-6, which also cleaves SNX2, did not fully abolish SNX2 proteolysis, suggesting that proteases upstream of this caspase may also participate in the cleavage of SNX2 in cells.

Furthermore, only initiator caspases were able to cleave SNX1, reinforcing the idea that initiators contribute to the cleavage of SNX proteins in cell death. This possibility is of particular interest as few substrates have been assigned to initiator caspases. The stimulation of death receptors causes their internalization via lipid rafts. Once internalized, sufficient caspase-8 activation occurs, allowing the activation of executioner caspases. HGF binding induces autophosphorylation of its receptor, promoting the activation of multiple signaling pathways.

In normal conditions, SNX1 and SNX2 associate with the retromer to mediate retrograde transport of cargo to the TGN and also participate in receptor recycling to the plasma membrane. SNX1 and SNX2 are two early endosome-localized proteins belonging to the SNX family of proteins, whose members are critical for protein trafficking steps within the endocytic pathway.

Our work demonstrates that SNX2 cleavage leads to dissociation from Vps35 and the delocalization of Vps26, suggesting the uncoupling of the endosomal cargo recognition machinery from the transport machinery itself. One aspect that may be affected by SNX cleavage is apoptosis via death receptors that requires their trafficking in endosomes, where the associated initiator caspase-8 activates the bulk of the executioner caspase-3 reviewed in Guicciardi et al.

Moreover, studies have demonstrated that caspase-3 immobilization via palmitoylation at the plasma membrane, where caspase-8 is initially recruited at the DISC, enhances its activation.

This suggests that co-localization of a caspase with specific substrates can result in more efficacious proteolysis. Although we have not yet assessed the role of SNX cleavage in modulating caspasemediated apoptosis, this avenue is appealing in light of our findings because SNX1 and SNX2 promote endosomal trafficking. Thus, we speculate that SNX1 and SNX2 cleavage by caspase-8, which we demonstrated are best performed by this caspase in vitro , is a means to stall internalized DISC in vesicles and further promote the activation of caspases.