Cell Death Protein 3 (Ced-3)
Apoptosis is a process through which an organism controls the number of cells in the various organs through a highly regulated form of cell death. The process is highly conserved, especially in invertebrates and mammals, and it takes place throughout their life. Apoptosis is mediated by cysteine-dependent aspartate-specific proteases (herein referred to as caspases), which are death-inducing proteases.
Cell death protein 3 (herein referred to as CED- 3) plays the role of a cysteine protease that regulates apoptosis by proteolytically activating or inactivating a substrate protein. It is noted that a potential substrate for this protease might be ced-4. Ced-3 is usually present during embryogenesis, but it may also persist during later stages of the organism’s development. Its concentration is high during embryogenesis stage, reducing as the organism develops. It belongs to peptidase C14A family, with a 1 CARD domain, and it may be regulated by phosphorylation. It is cleaved into 2 chains, which are cell death protein 3 subunit 1 and cell death protein 3 subunit 2.
The role that ced-3 plays in apoptosis has been extensively studies especially in nematode Caenorhabditis elegans. This is especially so given the fact that throughout the development of this nematode, the number of cells in the organs is highly controlled and almost all mature C. elegans contain the same number of cells in the various organs. In these organisms, ced-3 caspase is controlled to ensure that only those cells that are marked for death undergo apoptosis.
Ced-3 caspase in C. elegans contains significant homology to caspases 3 and 8 in mammals. Ced-3 is synthesized in the form of an inactive zymogen, ensuring that it is not active in cells not marked for apoptosis. When apoptosis is initiated, dimerization and autoproteolysis produce the large and small subunits which are the active components of this caspase. This is from the N-terminal prodomain of the caspase, during which process inactive monomers of the caspase are activated by oligomerized caspase 4. This process is similar to that of caspase 9 activation in higher organisms.
Caspase-8
By November 2009, 12 cysteine- aspartic proteases (caspases) have been documented in human beings. Caspases are classified into two groups, depending on the role that they play in apoptosis. The first is initiator or apical caspases, which cleaves inactive pro-forms of effector caspases, initiating the apoptosis process. The other group is called effector or executioner caspases, which cleaves other protein substrates that are found within the cell of the organism. This triggers the programmed death of the cell. Caspase 8 is an apical or initiator caspase.
During the apoptotic process, CASP8 has been shown to act on caspase 3. This protein has also been shown to interact with other agents such as CFLAR, PEA15, and BH3 interacting domain death agonists among others.
Like other caspases, CASP8 can be inhibited by viral actions in the organism. The virus can directly compromise the function of the caspase enzymes. One way through which viral-mediated inhibition of caspase can take place is through the interaction between the virus and the active site of the caspase. The virus can also assume the role of competitive inhibitors to molecules that signal the activation of the caspase. Studies in this field have identified four main groups of such virus-encoded inhibitors that interfere with the activation of caspases. The first is p35 family of inhibitors, inhibitors whose cellular homologs remain unknown so far. The second is a viral inhibitor of apoptosis proteins, also known as vIAPs, and thirdly the serine protease inhibitor of the serpin family. The fourth and last virus-encoded inhibitor is the Fas-associated death domain-like interleukin-1β-converting enzyme (FLICE) inhibitory proteins.
Baculovirus Lymantria dispar Multinucleocapsid nucleopolyhedrovirus Virus (LdMNPV)
It has been shown that baculoviruses form a large family of viruses that contain DNA protein. They especially infect arthropods, with high cases recorded in lepidopteran insects. LdMNPV is such one baculovirus that is made up of 161,046 bases with a G + C content of 57.5%. It also has 163 putative open reading frames (also referred to as ORFs) of ≥150 nucleotides.
Recent studies conducted on the LdMNPV genome have indicated that at least 9 percent of it is made up of 16 repeated genes that are linked to Autographa californica MNPV (AcMNPV).
Hundreds of insect species are infected by baculoviruses, and the variant of the virus have been shown to be dependent on the specificity of the insect’s species. Baculoviruses are also differentiated by the pathology of their infection cycle as well as the size of the genome and G + C content. AcMNPV is the most common baculovirus, and it shares some similarities with LdMNPV.
The genome of LdMNPV is larger than that of other baculoviruses such as AcMNPV, BmNPV and OpMNPV. Studies have shown that LdMNPV has 13 homologous regions (hrs), and out of the 163 ORFs it contains, 114 of them are related to those of AcMNPV.
LdMNPV has been put into commercial use, given the fact that it is regarded as one of the many viable microbial insecticides. For example, the USDA Forest Service has used it to control gypsy moth populations in forests. This is especially so during spot eradication in localities which are environmentally sensitive.
References
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Yan N, et al. Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature 2005;437:831–837.
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