Abstract
Stress signals cause abnormal proteins to accumulate in the endoplasmic reticulum (ER). Such stress is known as ER stress, which has been suggested to be involved in neurodegenerative diseases, diabetes, obesity and cancer. ER stress activates the unfolded protein response (UPR) to reduce levels of abnormal proteins by inducing the production of chaperon proteins such as GRP78, and to attenuate translation through the phosphorylation of eIF2α. However, excessive stress leads to apoptosis by generating transcription factors such as CHOP. Casein kinase 2 (CK2) is a serine/threonine kinase involved in regulating neoplasia, cell survival and viral infections. In the present study, we investigated a possible linkage between CK2 and ER stress using mouse primary cultured glial cells. 4,5,6,7-tetrabromobenzotriazole (TBB), a CK2-specific inhibitor, attenuated ER stress-induced XBP-1 splicing and subsequent induction of GRP78 expression, but was ineffective against ER stress-induced eIF2α phosphorylation and CHOP expression. Similar results were obtained when endogenous CK2 expression was knocked-down by siRNA. Immunohistochemical analysis suggested that CK2 was present at the ER. These results indicate CK2 to be linked with UPR and to resist ER stress by activating the XBP-1-GRP78 arm of UPR.
Highlights
Stress signals, which impair endoplasmic reticulum (ER) function, result in the accumulation of unfolded proteins
To evaluate the role of Casein kinase 2 (CK2) in the ER stress-induced activation of unfolded protein response (UPR), we exposed glial cells to ER stress-inducing reagents along with the CK2specific inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) [18], and examined the level of glucose-regulated protein 78 (GRP78)
Expression and Subcellular Distribution of CK2 As we found that CK2 would contribute to ER stress-induced activation of UPR via the XBP-1-GRP78 pathway, we investigated whether the expression of CK2 would be affected by ER stress
Summary
Stress signals, which impair endoplasmic reticulum (ER) function, result in the accumulation of unfolded proteins. When exposed to ER stress, cells activate several UPR pathways These responses include 1) increasing the folding capacity of unfolded proteins by releasing chaperon proteins, 2) inhibiting general protein translation to stop the production of unfolded proteins, and 3) promoting the degradation of unfolded proteins [1,2,3]. As components responsible for the activation of UPR, several ER stress-sensing proteins, which reside in the ER, have been identified: i.e. inositol-requiring protein-1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Activation of these stress-sensors eventually transmits stress signals to the nucleus [4]. The increase in eIF2 phosphorylation, paradoxically activates the CCAAT/enhancer-binding protein homologous protein (CHOP) promoter and results in production of CHOP, an apoptotic transcription factor [9]
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