Caspase‐12 and ER‐Stress‐Mediated Apoptosis

Abstract

The labyrinth of the endoplasmic reticulum (ER) interweaves the cytosol and connects to the nucleus, mitochondria, and the plasma membrane. In the lumen of the ER, the essential function of lipid synthesis, Ca(2+) storage, folding, and maturation of proteins take place. Therefore, the tight regulation and maintenance of ER homeostasis is vital. Disturbance of the Ca(2+) homeostasis during hypoxia, or imbalance between the demand and capacity of the protein-folding apparatus, initiates an adaptive response of the cell, termed the unfolded protein response (UPR, ER stress response). As a result, ER-localized chaperones are induced, protein synthesis is slowed down, and a protein degrading system is initiated. However, if the ER stress cannot be alleviated, it culminates in apoptosis. This paper reviews the newly outlined signaling pathways of the unfolded protein response and describes the central role of caspase-12 in the initiation of cell death. The complex role of the ER and its signaling pathways provides a novel angle on apoptosis research and may offer a key to apoptosis-associated diseases.

Overview of cell death signaling pathways

“…However, functional caspase-12 has only been cloned from the mouse and rat, and the existence of a human isoform of caspase-12 remains controversial. 209 Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease) and prion protein diseases all feature misfolded proteins and the aggregation of misfolded proteins. ER stress plays an important pathogenetic role in these diseases.…”

Aging Impairs the Unfolded Protein Response to Sleep Deprivation and Leads to Proapoptotic Signaling

“…All known caspases require cleavage adjacent to aspartates to liberate one large and one small subunit, which associate into a2b2 tetramer to form the active enzyme (for review, see Nunez et al, 1998;Thornberry and Lazebnik, 1998). Once activated, caspase-12 translocates from the ER to the cytosol in which it cleaves caspase-9, which induces the cleavage of caspase-3 in a cytochrome c-independent manner and activation of the rest of the apoptotic pathway (Szegezdi et al, 2003). We compared the amount of procaspase-12 and activated cleaved caspase-12 in young and aged control and 6 h sleep-deprived samples.…”

“…However, the ratio of cleaved caspase-12 to procaspase-12 was significantly higher in aged control animals (66.0 Ϯ 12.6%; n ϭ 6) compared with that in young control animals (36.0 Ϯ 8.5%; n ϭ 6; p ϭ 0.001). During cleavage, caspase-12 is activated and translocates from the ER to the cytosol in which it is reported to cleave caspase-9, which in turn activates caspase-3 and the rest of the caspase cascade (Morishima et al, 2002;Szegezdi et al, 2003).…”

“…Given that CHOP levels are increased, we examined next the expression of procaspase-12 and cleaved caspase-12, components of the second main ER stress-induced apoptotic pathway (Szegezdi et al, 2003). Caspase-12 is a member of the caspase family of cysteine proteases that are key mediators of programmed cell death or apoptosis.…”

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

“…5B). Caspase 12 is a mediator of the sarcoplasmic reticulum-mediated apoptosis pathway (25). Sarcoplasmic reticulum stress-induced apoptosis was recently demonstrated to contribute to heart failure following pressure overload (26).…”