New mitochondrial DNA synthesis enables NLRP3 inflammasome activation

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, Tatiana Kisseleva and Michael Karin ()
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Zhenyu Zhong: School of Medicine, University of California San Diego
Shuang Liang: School of Medicine, University of California San Diego
Elsa Sanchez-Lopez: School of Medicine, University of California San Diego
Feng He: School of Medicine, University of California San Diego
Shabnam Shalapour: School of Medicine, University of California San Diego
Xue-jia Lin: School of Medicine, University of California San Diego
Jerry Wong: School of Medicine, University of California San Diego
Siyuan Ding: Stanford University School of Medicine
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
Tatiana Kisseleva: School of Medicine, University of California San Diego
Michael Karin: School of Medicine, University of California San Diego

Nature, 2018, vol. 560, issue 7717, 198-203

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0372-z

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