CASP12
Неактивная каспаза-12 является белком, который кодируется геном CASP12. Не обладает протеазной активностью. Может снижать высвобождение цитокинов в ответ на бактериальный липополисахарид во время инфекций. Снижает активацию NF-kappa-B в ответ на TNF.
The CASP12 encodes caspase-12, which is one of the inflammatory group caspases. Caspase-12 is localized on the cytoplasmic side of the ER (endoplasmic-reticulum) membrane and is involved in the ER stress-induced apoptosis. Crystal structure analysis found that a caspase-associated recruitment domain (CARD), two catalytic domains, p20, and p10 in caspase-12. In humans, the caspase-12 gene has a single nucleotide polymorphism that facilitates the synthesis of either a truncated or full-length caspase-12 protein. When exposed to ER stresses, cytosolic calcium levels are increased, inducing the activation of m-calpain. Activated m-calpain cleaves Bcl-XL and proteolytically activates caspase-12. Takunari Yoneda et al. found that ER stress led to the dissociation of procaspase-12 from TRAF2 of the stable complex formed in unstressed cells and simultaneous dimerization (or oligomerization) of procaspase-12. Active caspase-12 translocates from the ER to the cytosol and activates caspase-9 independent of Apaf-1, followed by activation of caspase-3. The activation of executioner caspase-3 promotes the cleavage and degradation of downstream target molecules that are important for cellular survival, thus leading to apoptosis. Mice deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli. In addition to the essential role in apoptosis, caspase-12 also exerts roles in the inflammation. In humans, a caspase-12 isozyme functions as a dominant-negative regulator of the pro-inflammatory signaling pathway. Because it inhibits the activation of caspase-1 in inflammasome complexes, blocks the production of the pro-inflammatory cytokines IL-1β and IL-18, and disturbs the overall response to sepsis. |
