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CASP12
CASP12 Full Name
caspase 12 (gene/pseudogene)
CASP12 Introduction
One of the most idiosyncratic genes in the human genome encodes the protein known as caspase-12, whose gene is CASP12. Caspases are central effectors of a number of critical biological pathways, such as apoptosis, pyroptosis and inflammation. The evolution of caspase-12 is unusual because it is non-functional in the majority of humans for whom CASP12 is a pseudogene. This is due to a common SNP found in the coding region of CASP12—a C→T mutation, or T125C—which results in a premature stop codon. The resultant transcripts are largely truncated and do not result in functional proteins. However, in a substantial proportion of individuals of African ancestry, an ancestral allele remains that is capable of producing full-length, functional caspase-12 (sometimes denoted Casp12-L, or the long variant). The presence of the functional allele among sub-Saharan populations varies widely, which is likely the result of a selective sweep. This, in turn, suggests that after early human migration "Out of Africa", the quick fixation of a nonfunctional CASP12 allele gave the carriers a survival advantage, or, contrarily, the presence of functional caspase-12 was disadvantageous.
Caspase-12 when expressed as a full-length functional protein is known to have two related primary functions. It may mediate ER stress-induced apoptosis and it may negatively regulate innate immune responses. 1) Caspase-12 is an initiator caspase that is located in the ER membrane and is an important effector in the ER stress signaling pathway. It is induced upon extreme ER stress (e.g. resulting from a buildup of unfolded proteins) through pro-caspase-12 (zymogen) and, possibly, through adaptor protein binding (such as TRAF2) and proteolytic cleavage. Active caspase-12 can promote apoptosis through the activation of downstream caspase-9 (and executioner caspase-3) in a manner that is independent of the classical mitochondrial pathway (i.e. without the release of cytochrome c), directly or indirectly. 2) Functional caspase-12 is an important negative regulator of innate immune responses, acting as an "immune brake" on inflammation. Caspase-12 has been shown to directly bind to and inhibit caspase-1 within the inflammasome complex. Caspase-1 activation is needed for the processing and secretion of many important pro-inflammatory cytokines, including interleukin-1β and interleukin-18. By inhibiting caspase-1 activation, functional caspase-12 reduces the inflammatory response to, for instance, pathogen-associated molecular patterns such as bacterial LPS, which in turn substantially reduces IL-1β and IL-18 production and release.
Figure 1. The postadaptive phase of UPR. (Source: Szegezdi E, et al. 2003)
Repeated clinical reports have shown that carriers of functional Casp12-L allele are more prone to severe bacterial infections, worse disease outcomes and increased mortality in sepsis. The primary reason is the immunosuppressive role of caspase-12. Upon bacterial infection, the caspase-12 protein in individuals carrying functional CASP12 inhibits major innate immune signaling pathways leading to defective early production of key cytokines such as IL-1β, IL-18, and IFN-γ. This weakens the early immune response, decreases bacterial clearance, and increases the risk of uncontrolled infection leading to potentially fatal systemic inflammatory response syndrome (SIRS).
Alternate Names for CASP12
CASP12; caspase 12 (gene/pseudogene); CASP-12; CASP12P1; inactive caspase-12; caspase 12 pseudogene 1;
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