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

Author

Listed:
  • Wenjun Wang

    (Jinan University
    Jinan University)

  • Junyang Tan

    (Jinan University
    Jinan University)

  • Xiaomin Liu

    (Jinan University
    Jinan University)

  • Wenqi Guo

    (Jinan University
    Jinan University)

  • Mengmeng Li

    (Jinan University
    Jinan University)

  • Xinjie Liu

    (Jinan University
    Jinan University)

  • Yanyan Liu

    (Jinan University
    Jinan University)

  • Wenyu Dai

    (Jinan University
    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
    Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore)

  • Qinghua Zhou

    (Jinan University
    Jinan University
    Jinan University)

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.

Suggested Citation

  • 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 & Qinghua Zhou, 2023. "Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41757-x
    DOI: 10.1038/s41467-023-41757-x
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    References listed on IDEAS

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    2. Moritz Hunkeler & Anna Hagmann & Edward Stuttfeld & Mohamed Chami & Yakir Guri & Henning Stahlberg & Timm Maier, 2018. "Structural basis for regulation of human acetyl-CoA carboxylase," Nature, Nature, vol. 558(7710), pages 470-474, June.
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    1. Marta Llovera & Leonor Gouveia & Antonio Zorzano & Daniel Sanchis, 2024. "The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria," Nature Communications, Nature, vol. 15(1), pages 1-5, December.

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