Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress

Wenjun Wang (), Junyang Tan, Xiaomin Liu, Wenqi Guo, Mengmeng Li, Xinjie Liu, Yanyan Liu, Wenyu Dai, Liubing Hu, Yimin Wang, Qiuxia Lu, Wen Xing Lee, Hong-Wen Tang and Qinghua Zhou ()
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Wenjun Wang: Jinan University
Junyang Tan: Jinan University
Xiaomin Liu: Jinan University
Wenqi Guo: Jinan University
Mengmeng Li: Jinan University
Xinjie Liu: Jinan University
Yanyan Liu: Jinan University
Wenyu Dai: Jinan University
Liubing Hu: Jinan University
Yimin Wang: GeneMind Biosciences Company Limited
Qiuxia Lu: Chengdu University
Wen Xing Lee: Duke-NUS Medical School, 8 College Road
Hong-Wen Tang: Duke-NUS Medical School, 8 College Road
Qinghua Zhou: Jinan University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41757-x

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