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

Abstract

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis.

ATF6β Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions

“…First, we assessed ATF6β expression in the adult brains. Consistent with our recent report [19], in situ hybridization revealed that Atf6b mRNA was widely expressed in the brain, with relatively higher levels in the hippocampus and cerebellum in WT mice, while the signal was almost abolished in Atf6b -/mice (Fig. 1A).…”

“…1C), while expression of Hspa5 (GRP78), a major molecular chaperone in the ER, was increased in Atf6b -/mice (Fig. 1D) in all regions, as described in our recent report [19]. Consistently, paraventricular hypothalamic nucleus (PVN) CRT expression was reduced in Atf6b -/mice relative to WT mice (Figs.…”

“…3D). This may not be due to the impaired memory function, as we recently reported that hippocampal memory function, which was evaluated using the Morris water maze test, was not affected in Atf6b -/mice [19]. Collectively, these results indicate that ATF6β-de cient mice exhibited anxiety-like behaviors in approaching bright places, and hyperactivity under stress situations.…”

“…We previously reported that ATF6α contributes to neuronal survival and astroglial activation in neuropathological conditions such as brain ischemia, excitotoxity, and a Parkinson's disease model [15][16][17], although ATF6α enhances microglia-mediated neuroin ammation in experimental autoimmune encephalomyelitis [18]. Recently, we reported that calreticulin (CRT), an ER molecular chaperone with high Ca 2+ -binding capacity, is a unique target of ATF6β in the CNS, and that the ATF6β-CRT axis contributes to neuronal survival under ER stress and excitotoxicity by improving brain intracellular Ca 2+ homeostasis [19]. Although ATF6β is widely expressed in the brain and contributes to neuronal survival, its physiological role remains incompletely understood.…”

Genetic architecture of the HLA/MHC locus in cardiometabolic disease, severe mental illness, and related traits.

“…ATF6B (also called CREB-RP or CERBL1) encodes a transcription factor which, when activated in response to endoplasmic reticulum stress, increases transcription of genes involved in the unfolded protein response (https://www.ncbi.nlm.nih.gov/gene/1388). There is limited understanding of the role of the ATF6B protein, however it appears to protect neurons (30) and pancreatic beta cells (31) from endoplasmic reticulum stress-induced cell death, albeit the relative levels of ATF6A and ATF6B could be more important that levels of ATF6B alone (32). BAG6 (also called BAT3) is located within the HLA class III gene cluster and is implicated in many functions (reviewed in (33)) including apoptosis (34), removal of mitochondria (35) and neurodegeneration-associated protein aggregates (36), modulating immune (37) and anti-viral response (38), de ning dendritic cell functions (39) and energy switching in cardiomyocytes (40).…”