@article{a02dfde592164212831803bc1f3c6a30,
title = "New mitochondrial DNA synthesis enables NLRP3 inflammasome activation",
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.",
author = "Zhenyu Zhong and Shuang Liang and Elsa Sanchez-Lopez and Feng He and Shabnam Shalapour and Lin, {Xue jia} and Jerry Wong and Siyuan Ding and Ekihiro Seki and Bernd Schnabl and Hevener, {Andrea L.} and Greenberg, {Harry B.} and Tatiana Kisseleva and Michael Karin",
note = "Funding Information: Acknowledgements We thank eBioscience, Cell Signaling Technologies, Santa Cruz Technologies, and Thermo Fisher for gifts of reagents, and N. Yan and J. Rehwinkel for SAMHD1-deficient murine bone marrow. Z.Z. was supported by Cancer Research Institute (CRI) Irvington Fellowship, Prevent Cancer Foundation Board of Directors Research Fund, and American Association for the Study of Liver Diseases Pinnacle Research Award; F.H. was supported by Eli Lilly LIFA program; S.S. was supported by fellowships from CRI-Irvington and Prostate Cancer Foundation; J.W. was supported by a Canadian Institutes of Health Research fellowship (MFE-135425). Research was supported by NIH grants AI043477 and CA163798 to M.K., AA020172 and DK085252 to E.S., ES010337 to M.K. and E.S., DK109724 and P30DK063491 to A.L.H., DK099205, DK101737 and DK111866 to T.K., AA022614 to T.K. and M.K., Leukemia and Lymphoma Society SCOR grant 20132569 to T. Kipps and M.K., and the Alliance for Lupus Research grant 257214 and CART Foundation to M.K., who is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. Publisher Copyright: {\textcopyright} 2018, Springer Nature Limited.",
year = "2018",
month = aug,
day = "9",
doi = "10.1038/s41586-018-0372-z",
language = "English (US)",
volume = "560",
pages = "198--203",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7717",
}