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 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...

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Bibliographic Details
Published in:Scientific reports 2021-06, Vol.11 (1), p.13086-13086, Article 13086
Main Authors: Nguyen, Dinh Thi, Le, Thuong Manh, Hattori, Tsuyoshi, Takarada-Iemata, Mika, Ishii, Hiroshi, Roboon, Jureepon, Tamatani, Takashi, Kannon, Takayuki, Hosomichi, Kazuyoshi, Tajima, Atsushi, Taniuchi, Shusuke, Miyake, Masato, Oyadomari, Seiichi, Tanaka, Takashi, Kato, Nobuo, Saito, Shunsuke, Mori, Kazutoshi, Hori, Osamu
Format: Article
Language:English
Subjects:
631/378
631/80
Calcium (intracellular)
Calcium homeostasis
Calreticulin
Central nervous system
Death
Endoplasmic reticulum
Excitotoxicity
Hippocampus
Homeostasis
Humanities and Social Sciences
Mortality
multidisciplinary
Reagents
Science
Science (multidisciplinary)
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Summary: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 Ca 2+ -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 Ca 2+ 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 Ca 2+ -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 Ca 2+ homeostasis.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-92529-w