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Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells

Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to β-cell loss in mice. However, the mechanism by which Gsk-3 leads β-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and...

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Autores principales: Nagao, Yuko, Amo-Shiinoki, Kikuko, Nakabayashi, Hiroko, Hatanaka, Masayuki, Kondo, Manabu, Matsunaga, Kimie, Emoto, Masahiro, Okuya, Shigeru, Tanizawa, Yukio, Tanabe, Katsuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657557/
https://www.ncbi.nlm.nih.gov/pubmed/36362372
http://dx.doi.org/10.3390/ijms232113586
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author Nagao, Yuko
Amo-Shiinoki, Kikuko
Nakabayashi, Hiroko
Hatanaka, Masayuki
Kondo, Manabu
Matsunaga, Kimie
Emoto, Masahiro
Okuya, Shigeru
Tanizawa, Yukio
Tanabe, Katsuya
author_facet Nagao, Yuko
Amo-Shiinoki, Kikuko
Nakabayashi, Hiroko
Hatanaka, Masayuki
Kondo, Manabu
Matsunaga, Kimie
Emoto, Masahiro
Okuya, Shigeru
Tanizawa, Yukio
Tanabe, Katsuya
author_sort Nagao, Yuko
collection PubMed
description Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to β-cell loss in mice. However, the mechanism by which Gsk-3 leads β-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and insulinoma cells. We used insulinoma cells derived from Akita mice as a model of genetic ER stress. Gsk-3 activity was blocked by treating with Gsk-3 inhibitors or by introducing catalytically inactive Gsk-3β. Gsk-3 inhibition prevented proteasomal degradation of activating transcriptional factor 4 (ATF4) and alleviated apoptosis. We found that ATF4-S214 was phosphorylated by Gsk-3, and that this was required for a binding of ATF4 with βTrCP, which mediates polyubiquitination. The anti-apoptotic effect of Gsk-3 inhibition was attenuated by introducing DN-ATF4 or by knockdown of ATF4. Mechanistically, Gsk-3 inhibition modulated transcription targets of ATF4 and in turn facilitated dephosphorylation of eIF2α, altering the protein translational dynamism under ER stress. These observations were reproduced in the Akita mouse-derived cells. Thus, these results reveal the role of Gsk-3 in the regulation of the integrated stress response, and provide a rationale for inhibiting this enzyme to prevent β-cell death under ER stress conditions.
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spelling pubmed-96575572022-11-15 Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells Nagao, Yuko Amo-Shiinoki, Kikuko Nakabayashi, Hiroko Hatanaka, Masayuki Kondo, Manabu Matsunaga, Kimie Emoto, Masahiro Okuya, Shigeru Tanizawa, Yukio Tanabe, Katsuya Int J Mol Sci Article Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to β-cell loss in mice. However, the mechanism by which Gsk-3 leads β-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and insulinoma cells. We used insulinoma cells derived from Akita mice as a model of genetic ER stress. Gsk-3 activity was blocked by treating with Gsk-3 inhibitors or by introducing catalytically inactive Gsk-3β. Gsk-3 inhibition prevented proteasomal degradation of activating transcriptional factor 4 (ATF4) and alleviated apoptosis. We found that ATF4-S214 was phosphorylated by Gsk-3, and that this was required for a binding of ATF4 with βTrCP, which mediates polyubiquitination. The anti-apoptotic effect of Gsk-3 inhibition was attenuated by introducing DN-ATF4 or by knockdown of ATF4. Mechanistically, Gsk-3 inhibition modulated transcription targets of ATF4 and in turn facilitated dephosphorylation of eIF2α, altering the protein translational dynamism under ER stress. These observations were reproduced in the Akita mouse-derived cells. Thus, these results reveal the role of Gsk-3 in the regulation of the integrated stress response, and provide a rationale for inhibiting this enzyme to prevent β-cell death under ER stress conditions. MDPI 2022-11-05 /pmc/articles/PMC9657557/ /pubmed/36362372 http://dx.doi.org/10.3390/ijms232113586 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nagao, Yuko
Amo-Shiinoki, Kikuko
Nakabayashi, Hiroko
Hatanaka, Masayuki
Kondo, Manabu
Matsunaga, Kimie
Emoto, Masahiro
Okuya, Shigeru
Tanizawa, Yukio
Tanabe, Katsuya
Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells
title Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells
title_full Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells
title_fullStr Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells
title_full_unstemmed Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells
title_short Gsk-3-Mediated Proteasomal Degradation of ATF4 Is a Proapoptotic Mechanism in Mouse Pancreatic β-Cells
title_sort gsk-3-mediated proteasomal degradation of atf4 is a proapoptotic mechanism in mouse pancreatic β-cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657557/
https://www.ncbi.nlm.nih.gov/pubmed/36362372
http://dx.doi.org/10.3390/ijms232113586
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