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New mitochondrial DNA synthesis enables NLRP3 inflammasome activation

Author

Listed:
  • Zhenyu Zhong

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego)

  • Shuang Liang

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego)

  • Elsa Sanchez-Lopez

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego)

  • Feng He

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego)

  • Shabnam Shalapour

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego)

  • Xue-jia Lin

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego
    Biomedical Translational Research Institute and the First Affiliated Hospital, Jinan University)

  • Jerry Wong

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego)

  • Siyuan Ding

    (Stanford University School of Medicine
    Stanford University School of Medicine
    VA Palo Alto Health Care System)

  • Ekihiro Seki

    (Division of Gastroenterology, Cedars-Sinai Medical Center)

  • Bernd Schnabl

    (School of Medicine, University of California San Diego)

  • Andrea L. Hevener

    (Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California at Los Angeles)

  • Harry B. Greenberg

    (Stanford University School of Medicine
    Stanford University School of Medicine
    VA Palo Alto Health Care System)

  • Tatiana Kisseleva

    (School of Medicine, University of California San Diego)

  • Michael Karin

    (School of Medicine, University of California San Diego
    School of Medicine, University of California San Diego)

Abstract

Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.

Suggested Citation

  • Zhenyu Zhong & Shuang Liang & Elsa Sanchez-Lopez & Feng He & Shabnam Shalapour & Xue-jia Lin & Jerry Wong & Siyuan Ding & Ekihiro Seki & Bernd Schnabl & Andrea L. Hevener & Harry B. Greenberg & Tatian, 2018. "New mitochondrial DNA synthesis enables NLRP3 inflammasome activation," Nature, Nature, vol. 560(7717), pages 198-203, August.
    • Handle: RePEc:nat:nature:v:560:y:2018:i:7717:d:10.1038_s41586-018-0372-z
    DOI: 10.1038/s41586-018-0372-z
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    Cited by:

    1. Niranjana Natarajan & Jonathan Florentin & Ebin Johny & Hanxi Xiao & Scott Patrick O’Neil & Liqun Lei & Jixing Shen & Lee Ohayon & Aaron R. Johnson & Krithika Rao & Xiaoyun Li & Yanwu Zhao & Yingze Zh, 2024. "Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Longjun Li & Rudi Mao & Shenli Yuan & Qingqing Xie & Jinyu Meng & Yu Gu & Siyu Tan & Xiaoqing Xu & Chengjiang Gao & Hongbin Liu & Chunhong Ma & Si Ming Man & Xiangbo Meng & Tao Xu & Xiaopeng Qi, 2024. "NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Kelvin Ka Lok Wu & KeKao Long & Huige Lin & Parco Ming Fai Siu & Ruby Lai Chong Hoo & Dewei Ye & Aimin Xu & Kenneth King Yip Cheng, 2021. "The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Naijun Miao & Zhuning Wang & Qinlan Wang & Hongyan Xie & Ninghao Yang & Yanzhe Wang & Jin Wang & Haixia Kang & Wenjuan Bai & Yuanyuan Wang & Rui He & Kepeng Yan & Yang Wang & Qiongyi Hu & Zhaoyuan Liu, 2023. "Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Shouya Feng & Daniel Enosi Tuipulotu & Abhimanu Pandey & Weidong Jing & Cheng Shen & Chinh Ngo & Melkamu B. Tessema & Fei-Ju Li & Daniel Fox & Anukriti Mathur & Anyang Zhao & Runli Wang & Klaus Pfeffe, 2022. "Pathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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