Protective effect of CK2 against endoplasmic reticulum stress in pancreatic β cells.

Abstract

Endoplasmic reticulum (ER) stress due to obesity or systemic insulin resistance is an important pathogenic factor that could lead to pancreatic β-cell failure. We have previously reported that CCAAT/enhancer-binding protein β (C/EBPβ) is highly induced by ER stress in pancreatic β cells. Moreover, its accumulation hampers the response of these cells to ER stress by inhibiting the induction of the molecular chaperone 78 kDa glucose-regulated protein (GRP78). We also demonstrated that C/EBPβ is phosphorylated by CK2, which is reportedly associated with the ER stress signal. In the present study, we aimed to clarify the mechanisms underlying the effect of CK2 on pancreatic β cells using a CK2-specific inhibitor, CX4945, and shRNA-mediated knockdown and overexpression of CK2β, the regulatory subunit of CK2. The results indicate that CK2 was activated in MIN6 cells under ER stress and in pancreatic β cells of a diabetic mouse model. Under normal conditions, CK2 interacted with FL-ATF6α in MIN6 cells and regulated the expression of GRP78 and ERAD-associated proteins. Mechanistically, CK2 activation in MIN6 cells upon the overexpression of the CK2β subunit reduced ER stress signals and the accumulation of unfolded proteins via an increase in GRP78 and ERAD-associated protein levels. These results highlight the important role of CK2 in protecting against ER stress-induced apoptosis by regulating GRP78 and ERAD proteins. CK2 contributed to the clearance of unfolded or misfolded proteins in MIN6 cells under both normal and ER stress conditions. Therefore, CK2 activation could be a promising novel approach for preventing type 2 diabetes.

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-024-00775-w.