Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death

Abstract

Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-β (Aβ)–induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Aβ, and Aβ-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease.

Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro

“…NEFA induce ER stress response genes (nuclear factor κB [NFκB]) in beta cells [45] in a similar, but not identical, way to that of cytokines (IL-1β, TNF-α) [44]; these effects were shown to be more pronounced in cells exposed to palmitic than oleic acid [44,45]. TGs that are rich in saturated fatty acids remain in the ER of cells and could trigger induction of ER stress response proteins, leading to apoptotic death [46]. Recently it has been shown that factors related to oxidative stress (reactive oxygen species and nitric oxide) and palmitate-derived ceramides are not causative factors for loss of GSIS following chronic exposure to NEFA [37].…”

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

“…Human caspase-4 is a potential homolog of murine caspase-12 involved in ER stress (Hitomi et al, 2004). As shown in Figure 2b, edelfosine treatment induced caspase-4 activation, as assessed by cleavage of procaspase-4 into the 20-kDa active form.…”

“…Nevertheless, ER stress sensors do not directly cause cell death, but rather initiate the activation of downstream molecules, such as CHOP (C/EBP homologus protein)/ growth arrest and DNA damage-inducible gene 153 (GADD153) or c-Jun NH 2 -terminal kinase (JNK), which further push the cell down the path of death. Three main pathways of ER stress-induced apoptosis are known, namely: (1) upregulation of the transcription factor CHOP/GADD153 (Ron and Habener, 1992); (2) JNK activation (Urano et al, 2000); (3) activation of caspase-12 in murine systems or caspase-4 in human cells (Hitomi et al, 2004). These three pathways all end in caspase cascade activation followed by the induction of apoptosis.…”

ER stress and neurodegenerative diseases

“…Caspase-4 is increased in AD brains, suggesting that this caspase may play a role in ER stress-induced cell death. 25 Recent studies on the UPR revealed increased levels of Bip/Grp78 and the protein kinase, Perk in AD brain. 44 This shows the occurrence of ER stress in AD although the initial changes in these UPR mediators may reflect neuroprotection rather than nerve cell degeneration.…”

“…10,24 It is possible that other caspases take over the function of caspase-12 in humans, as suggested for the human caspase-4. 25 However, the role of caspases-12 and -4 as initiators of ER stress-induced cell death is a matter of current debate. 24 Procaspase-2 and a novel procaspase-8 isoform are also associated with the ER in some cell types.…”