IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-41757-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-41757-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-41757-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. Santos A. Susin & Hans K. Lorenzo & Naoufal Zamzami & Isabel Marzo & Bryan E. Snow & Greg M. Brothers & Joan Mangion & Etienne Jacotot & Paola Costantini & Markus Loeffler & Nathanael Larochette & Dav, 1999. "Molecular characterization of mitochondrial apoptosis-inducing factor," Nature, Nature, vol. 397(6718), pages 441-446, February.
    3. Rajat Singh & Susmita Kaushik & Yongjun Wang & Youqing Xiang & Inna Novak & Masaaki Komatsu & Keiji Tanaka & Ana Maria Cuervo & Mark J. Czaja, 2009. "Autophagy regulates lipid metabolism," Nature, Nature, vol. 458(7242), pages 1131-1135, April.
    4. C. Martinez Calejman & S. Trefely & S. W. Entwisle & A. Luciano & S. M. Jung & W. Hsiao & A. Torres & C. M. Hung & H. Li & N. W. Snyder & J. Villén & K. E. Wellen & D. A. Guertin, 2020. "mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Lin-lin Zhao & Ru Chen & Ziyu Bai & Junyi Liu & Yuhao Zhang & Yicheng Zhong & Meng-xiang Sun & Peng Zhao, 2024. "Autophagy-mediated degradation of integumentary tapetum is critical for embryo pattern formation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Hong Huang & Qinqin Ouyang & Min Zhu & Haijia Yu & Kunrong Mei & Rong Liu, 2021. "mTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Elodie Mailler & Carlos M. Guardia & Xiaofei Bai & Michal Jarnik & Chad D. Williamson & Yan Li & Nunziata Maio & Andy Golden & Juan S. Bonifacino, 2021. "The autophagy protein ATG9A enables lipid mobilization from lipid droplets," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    4. Guanlan Hu & Catriona Ling & Lijun Chi & Mehakpreet K. Thind & Samuel Furse & Albert Koulman & Jonathan R. Swann & Dorothy Lee & Marjolein M. Calon & Celine Bourdon & Christian J. Versloot & Barbara M, 2022. "The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Charlotte M. François & Thomas Pihl & Marion Dunoyer de Segonzac & Chloé Hérault & Bruno Hudry, 2023. "Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Yun Seok Kim & Bongsub Ko & Da Jung Kim & Jihoon Tak & Chang Yeob Han & Joo-Youn Cho & Won Kim & Sang Geon Kim, 2022. "Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    7. Denisa Margină & Anca Ungurianu & Carmen Purdel & Dimitris Tsoukalas & Evangelia Sarandi & Maria Thanasoula & Fotios Tekos & Robin Mesnage & Demetrios Kouretas & Aristidis Tsatsakis, 2020. "Chronic Inflammation in the Context of Everyday Life: Dietary Changes as Mitigating Factors," IJERPH, MDPI, vol. 17(11), pages 1-27, June.
    8. Hejazi Keyvan & Fathi Mehrdad & Salkhord Mahsa & Dastani Maryam, 2021. "The Effect of Eight Weeks of Combined Training (Endurance-Intermittent Resistance and Endurance-Continuous Resistance) on Coagulation, Fibrinolytic and Lipid Profiles of Overweight Women," Polish Journal of Sport and Tourism, Sciendo, vol. 28(4), pages 3-9, December.
    9. Zhen Yuan & Kun Cai & Jiajia Li & Ruifeng Chen & Fuhai Zhang & Xuan Tan & Yaming Jiu & Haishuang Chang & Bing Hu & Weiyi Zhang & Binbin Ding, 2024. "ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    10. King Hang Tommy Mau & Donja Karimlou & David Barneda & Vincent Brochard & Christophe Royer & Bryony Leeke & Roshni A. Souza & Mélanie Pailles & Michelle Percharde & Shankar Srinivas & Alice Jouneau & , 2022. "Dynamic enlargement and mobilization of lipid droplets in pluripotent cells coordinate morphogenesis during mouse peri-implantation development," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    11. Alexander J. Hu & Wei Li & Calvin Dinh & Yongzhao Zhang & Jamie K. Hu & Stefano G. Daniele & Xiaoli Hou & Zixuan Yang & John M. Asara & Guo-fu Hu & Stephen R. Farmer & Miaofen G. Hu, 2024. "CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    12. Odeta Meçe & Diede Houbaert & Maria-Livia Sassano & Tania Durré & Hannelore Maes & Marco Schaaf & Sanket More & Maarten Ganne & Melissa García-Caballero & Mila Borri & Jelle Verhoeven & Madhur Agrawal, 2022. "Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    13. Xiaowei Sun & Jie Shen & Norbert Perrimon & Xue Kong & Dan Wang, 2023. "The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    14. Zhenzhen Zi & Zhuzhen Zhang & Qiang Feng & Chiho Kim & Xu-Dong Wang & Philipp E. Scherer & Jinming Gao & Beth Levine & Yonghao Yu, 2022. "Quantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    15. Eric M. Lynch & Heather Hansen & Lauren Salay & Madison Cooper & Stepan Timr & Justin M. Kollman & Bradley A. Webb, 2024. "Structural basis for allosteric regulation of human phosphofructokinase-1," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    16. Scotland E. Farley & Jennifer E. Kyle & Hans C. Leier & Lisa M. Bramer & Jules B. Weinstein & Timothy A. Bates & Joon-Yong Lee & Thomas O. Metz & Carsten Schultz & Fikadu G. Tafesse, 2022. "A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Yoshito Minami & Atsushi Hoshino & Yusuke Higuchi & Masahide Hamaguchi & Yusaku Kaneko & Yuhei Kirita & Shunta Taminishi & Toshiyuki Nishiji & Akiyuki Taruno & Michiaki Fukui & Zoltan Arany & Satoaki , 2023. "Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. Donghai Cui & Zixiang Wang & Qianli Dang & Jing Wang & Junchao Qin & Jianping Song & Xiangyu Zhai & Yachao Zhou & Ling Zhao & Gang Lu & Hongbin Liu & Gang Liu & Runping Liu & Changshun Shao & Xiyu Zha, 2023. "Spliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    19. Jialiu Zeng & Rebeca Acin-Perez & Essam A. Assali & Andrew Martin & Alexandra J. Brownstein & Anton Petcherski & Lucía Fernández-del-Rio & Ruiqing Xiao & Chih Hung Lo & Michaël Shum & Marc Liesa & Xue, 2023. "Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. Leslie A. Rowland & Adilson Guilherme & Felipe Henriques & Chloe DiMarzio & Sean Munroe & Nicole Wetoska & Mark Kelly & Keith Reddig & Gregory Hendricks & Meixia Pan & Xianlin Han & Olga R. Ilkayeva &, 2023. "De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41757-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.