The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6β is largely unknown. Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin, a molecular chaperone in the ER with a high Ca ²⁺ -binding capacity. Calreticulin expression was reduced to ~50% in the central nervous system of Atf6b ^−/− mice, and restored by ATF6β. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca ²⁺ stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6β, calreticulin, Ca ²⁺ -modulating reagents such as BAPTA-AM and 2-APB, and ER stress inhibitor salubrinal. In vivo , kainate-induced neuronal death was enhanced in hippocampi of Atf6b ^−/− and Calr ^+/− mice, and restored by 2-APB and salubrinal. These results suggest that the ATF6β-calreticulin axis plays a critical role in the neuronal survival by improving Ca ²⁺ homeostasis under ER stress.