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Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress
Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, littl...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550995/ https://www.ncbi.nlm.nih.gov/pubmed/37794041 http://dx.doi.org/10.1038/s41467-023-41757-x |
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author | Wang, Wenjun Tan, Junyang Liu, Xiaomin Guo, Wenqi Li, Mengmeng Liu, Xinjie Liu, Yanyan Dai, Wenyu Hu, Liubing Wang, Yimin Lu, Qiuxia Lee, Wen Xing Tang, Hong-Wen Zhou, Qinghua |
author_facet | Wang, Wenjun Tan, Junyang Liu, Xiaomin Guo, Wenqi Li, Mengmeng Liu, Xinjie Liu, Yanyan Dai, Wenyu Hu, Liubing Wang, Yimin Lu, Qiuxia Lee, Wen Xing Tang, Hong-Wen Zhou, Qinghua |
author_sort | Wang, Wenjun |
collection | PubMed |
description | Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice. |
format | Online Article Text |
id | pubmed-10550995 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-105509952023-10-06 Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress Wang, Wenjun Tan, Junyang Liu, Xiaomin Guo, Wenqi Li, Mengmeng Liu, Xinjie Liu, Yanyan Dai, Wenyu Hu, Liubing Wang, Yimin Lu, Qiuxia Lee, Wen Xing Tang, Hong-Wen Zhou, Qinghua Nat Commun Article Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice. Nature Publishing Group UK 2023-10-04 /pmc/articles/PMC10550995/ /pubmed/37794041 http://dx.doi.org/10.1038/s41467-023-41757-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wang, Wenjun Tan, Junyang Liu, Xiaomin Guo, Wenqi Li, Mengmeng Liu, Xinjie Liu, Yanyan Dai, Wenyu Hu, Liubing Wang, Yimin Lu, Qiuxia Lee, Wen Xing Tang, Hong-Wen Zhou, Qinghua Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress |
title | Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress |
title_full | Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress |
title_fullStr | Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress |
title_full_unstemmed | Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress |
title_short | Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress |
title_sort | cytoplasmic endonuclease g promotes nonalcoholic fatty liver disease via mtorc2-akt-acly and endoplasmic reticulum stress |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550995/ https://www.ncbi.nlm.nih.gov/pubmed/37794041 http://dx.doi.org/10.1038/s41467-023-41757-x |
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