Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

Abstract

ER stress-induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress-mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress-induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/ calmodulin-dependent protein kinase IIγ (CaMKIIγ) and JNK. Remarkably, CaMKIIγ was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress-induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKIIγ-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis.

Protein Folding and Quality Control in the ER

“…Ero1a is induced by the CHOP-dependent stress response and hyperoxidizes the ER environment, which indirectly activates IP3R1 and releases Ca 2þ into the cytosol ). The released Ca 2þ activates calcium/calmodulin-dependent protein kinase II (CaMKII), which triggers apoptosis through both mitochondrial pathways and death receptor (Timmins et al 2009). Thus, redox and Ca 2þ homeostasis are interrelated in both a physical and physiological context.…”

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B 4 synthesis by inhibiting a calcium-activated kinase pathway

“…For example, CaMKII triggers endoplasmic reticulum-stress-induced apoptosis in macrophages (36), which could be important in diseases in which leukocyte apoptosis and secondary necrosis underlie the pathology, such as advanced atherosclerosis and certain autoimmune diseases (37,38). Moreover, in the setting of obesity, CaMKII promotes excessive hepatic glucose production and impairs hepatic insulin signaling by activating a p38-MK2-mediated pathway (29,30).…”

Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia

“…The extent of GluK2 Q/R editing is significantly decreased in ischemic vulnerable regions, including the hippocampus (38) 2+ increase, which activates calcineurin/nuclear factor of activated T cells (NFAT) (22,39). CaMKII/JNK and calcineurin/NFAT-induced up-regulation of Fas/FasL is involved in cell apoptosis (40,41). In addition, activated calcineurin may be involved in the endocytosis of kainate receptors through the dephosphorylation of endocytic proteins such as amphiphysin I and dynamin I (42,43).…”