New mitochondrial DNA synthesis enables NLRP3 inflammasome activation

By Zhenyu Zhong, Shuang Liang, E. Sanchez-Lopez, Feng He, S. Shalapour, Xue-jia Lin, J. Wong, Siyuan Ding, E. Seki, B. Schnabl and 4 more. Nature, 2018

1,040 citations recorded by the source corpus.

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. New mitochondrial DNA synthesis links the priming and activation of the NLRP3 inflammasome.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c4a4d550e149b1ed776843ab9ae5b053dbcb99b6

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In Immunology

1. S. Tait
2. Joel S. Riley
3. Yuan He

In Molecular Biology

1. S. Tait
2. J. K. Kim
3. Joel S. Riley
4. C. Sasakawa
5. E. Jo
6. Yuan He

Citations in the corpus

• An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “More recently, it was shown that mtDNA synthesis following TLR signaling can lead to the formation of oxidized mtDNA fragments that lead to inflammasome activation, indicating that these fragments are critical components of the NLRP3 machinery.(138,139) Severe fever with thrombocytopenia syndrome (S”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “Additionally, a recent study shows that priming signals downstream of TLR4 activate transcriptional factor IRF1 to induce the synthesis of mitochondrial DNA (mtDNA), which is required for NLRP3 inflammasome activation [47].”
• Mitochondrial DNA in inflammation and immunity (2020, positive): “However, the role of NLRP3 as a direct sensor of DNA is contentious, as many disparate signals have been reported as the common signal for NLRP3 activation [144].”