New mitochondrial DNA synthesis enables NLRP3 inflammasome activation

  • Nature. 2018 Aug;560(7717):198-203. doi: 10.1038/s41586-018-0372-z.
Zhenyu Zhong  1  2 ,  Shuang Liang  3  4 ,  Elsa Sanchez-Lopez  1  2 ,  Feng He  1  2 ,  Shabnam Shalapour  1  2 ,  Xue-Jia Lin  1  2  5 ,  Jerry Wong  1  2 ,  Siyuan Ding  6  7  8 ,  Ekihiro Seki  9 ,  Bernd Schnabl  3 ,  Andrea L Hevener  10 ,  Harry B Greenberg  6  7  8 ,  Tatiana Kisseleva  4 ,  Michael Karin  11  12
Affiliations
  • 1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 2. Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 3. Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 4. Department of Surgery, School of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 5. Biomedical Translational Research Institute and the First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 6. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • 7. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 8. VA Palo Alto Health Care System, Palo Alto, CA, USA.
  • 9. Department of Medicine, Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 10. Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
  • 11. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].
  • 12. Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].
PMID: 30046112 DOI: 10.1038/s41586-018-0372-z
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.