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 regu...

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Autores principales:	Dinh Thi Nguyen, Thuong Manh Le, Tsuyoshi Hattori, Mika Takarada-Iemata, Hiroshi Ishii, Jureepon Roboon, Takashi Tamatani, Takayuki Kannon, Kazuyoshi Hosomichi, Atsushi Tajima, Shusuke Taniuchi, Masato Miyake, Seiichi Oyadomari, Takashi Tanaka, Nobuo Kato, Shunsuke Saito, Kazutoshi Mori, Osamu Hori
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b4c6a06dddf248b4b95c7df5bc72b98a
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spelling	oai:doaj.org-article:b4c6a06dddf248b4b95c7df5bc72b98a2021-12-02T17:44:54ZThe ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity10.1038/s41598-021-92529-w2045-2322https://doaj.org/article/b4c6a06dddf248b4b95c7df5bc72b98a2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92529-whttps://doaj.org/toc/2045-2322Abstract 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.Dinh Thi NguyenThuong Manh LeTsuyoshi HattoriMika Takarada-IemataHiroshi IshiiJureepon RoboonTakashi TamataniTakayuki KannonKazuyoshi HosomichiAtsushi TajimaShusuke TaniuchiMasato MiyakeSeiichi OyadomariTakashi TanakaNobuo KatoShunsuke SaitoKazutoshi MoriOsamu HoriNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dinh Thi Nguyen Thuong Manh Le Tsuyoshi Hattori Mika Takarada-Iemata Hiroshi Ishii Jureepon Roboon Takashi Tamatani Takayuki Kannon Kazuyoshi Hosomichi Atsushi Tajima Shusuke Taniuchi Masato Miyake Seiichi Oyadomari Takashi Tanaka Nobuo Kato Shunsuke Saito Kazutoshi Mori Osamu Hori The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
description	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.
format	article
author	Dinh Thi Nguyen Thuong Manh Le Tsuyoshi Hattori Mika Takarada-Iemata Hiroshi Ishii Jureepon Roboon Takashi Tamatani Takayuki Kannon Kazuyoshi Hosomichi Atsushi Tajima Shusuke Taniuchi Masato Miyake Seiichi Oyadomari Takashi Tanaka Nobuo Kato Shunsuke Saito Kazutoshi Mori Osamu Hori
author_facet	Dinh Thi Nguyen Thuong Manh Le Tsuyoshi Hattori Mika Takarada-Iemata Hiroshi Ishii Jureepon Roboon Takashi Tamatani Takayuki Kannon Kazuyoshi Hosomichi Atsushi Tajima Shusuke Taniuchi Masato Miyake Seiichi Oyadomari Takashi Tanaka Nobuo Kato Shunsuke Saito Kazutoshi Mori Osamu Hori
author_sort	Dinh Thi Nguyen
title	The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
title_short	The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
title_full	The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
title_fullStr	The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
title_full_unstemmed	The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
title_sort	atf6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b4c6a06dddf248b4b95c7df5bc72b98a
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The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

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