New mitochondrial DNA synthesis enables NLRP3 inflammasome activation
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 inflammas...
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| Veröffentlicht in: | Nature (London) 2018-08, Vol.560 (7717), p.198-203 |
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| creator | Zhong, Zhenyu Liang, Shuang Sanchez-Lopez, Elsa He, Feng Shalapour, Shabnam Lin, Xue-jia Wong, Jerry Ding, Siyuan Seki, Ekihiro Schnabl, Bernd Hevener, Andrea L. Greenberg, Harry B. Kisseleva, Tatiana Karin, Michael |
| description | 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. |
| doi_str_mv | 10.1038/s41586-018-0372-z |
| format | Article |
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New mitochondrial DNA synthesis links the priming and activation of the NLRP3 inflammasome.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-018-0372-z</identifier><identifier>PMID: 30046112</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/250/256/2177 ; 631/250/262/2106/2517 ; 96/1 ; 96/106 ; 96/109 ; 96/31 ; 96/34 ; 96/44 ; 96/63 ; 96/95 ; Adapters ; Adaptor proteins ; Alzheimer's disease ; Analysis ; Animals ; Apoptosis ; Biocatalysis ; Catalysis ; Catalytic activity ; Cell activation ; Chronic diseases ; Chronic illnesses ; Cytochrome ; Cytological research ; Cytosol - metabolism ; Deoxyribonucleic acid ; Deoxyribonucleotides ; Dependence ; DNA ; DNA biosynthesis ; DNA synthesis ; DNA, Mitochondrial - biosynthesis ; Enzymes ; Humanities and Social Sciences ; Inflammasomes ; Inflammasomes - metabolism ; Inflammation ; Interferon regulatory factor 1 ; Interferon Regulatory Factor-1 - metabolism ; Kinases ; Lipopolysaccharides - pharmacology ; Macrophages ; Macrophages - cytology ; Macrophages - drug effects ; Mice ; Mitochondria ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondrial DNA ; multidisciplinary ; MyD88 protein ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; Nucleoside-Phosphate Kinase - genetics ; Nucleoside-Phosphate Kinase - metabolism ; Oxidation-Reduction ; Physiological aspects ; Receptors ; Science ; Science (multidisciplinary) ; Signal Transduction ; Synthesis ; Toll-like receptors ; Toll-Like Receptors - immunology ; Transcription ; Transcription factors ; Type 2 diabetes</subject><ispartof>Nature (London), 2018-08, Vol.560 (7717), p.198-203</ispartof><rights>Springer Nature Limited 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 9, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c739t-d3c4b46465557c4adf0d6614772a26d6717dd5f0c2e8d6ce6853ebf5b1eb09873</citedby><cites>FETCH-LOGICAL-c739t-d3c4b46465557c4adf0d6614772a26d6717dd5f0c2e8d6ce6853ebf5b1eb09873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-018-0372-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-018-0372-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30046112$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhong, Zhenyu</creatorcontrib><creatorcontrib>Liang, Shuang</creatorcontrib><creatorcontrib>Sanchez-Lopez, Elsa</creatorcontrib><creatorcontrib>He, Feng</creatorcontrib><creatorcontrib>Shalapour, Shabnam</creatorcontrib><creatorcontrib>Lin, Xue-jia</creatorcontrib><creatorcontrib>Wong, Jerry</creatorcontrib><creatorcontrib>Ding, Siyuan</creatorcontrib><creatorcontrib>Seki, Ekihiro</creatorcontrib><creatorcontrib>Schnabl, Bernd</creatorcontrib><creatorcontrib>Hevener, Andrea L.</creatorcontrib><creatorcontrib>Greenberg, Harry B.</creatorcontrib><creatorcontrib>Kisseleva, Tatiana</creatorcontrib><creatorcontrib>Karin, Michael</creatorcontrib><title>New mitochondrial DNA synthesis enables NLRP3 inflammasome activation</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>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.</description><subject>631/250/256/2177</subject><subject>631/250/262/2106/2517</subject><subject>96/1</subject><subject>96/106</subject><subject>96/109</subject><subject>96/31</subject><subject>96/34</subject><subject>96/44</subject><subject>96/63</subject><subject>96/95</subject><subject>Adapters</subject><subject>Adaptor proteins</subject><subject>Alzheimer's disease</subject><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biocatalysis</subject><subject>Catalysis</subject><subject>Catalytic activity</subject><subject>Cell activation</subject><subject>Chronic diseases</subject><subject>Chronic illnesses</subject><subject>Cytochrome</subject><subject>Cytological research</subject><subject>Cytosol - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>Deoxyribonucleotides</subject><subject>Dependence</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA synthesis</subject><subject>DNA, Mitochondrial - 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immunology</subject><subject>Transcription</subject><subject>Transcription factors</subject><subject>Type 2 diabetes</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kstuEzEUhi0EomnhAdigEWzKYoov40s2SFEpUCkKqMDa8thnElczdjqeKbRPj6OUtkFBXljy-c5_Lv4RekXwCcFMvU8V4UqUmKgSM0nL2ydoQiopykoo-RRNMKY5opg4QIcpXWKMOZHVc3TAMK4EIXSCzhbwq-j8EO0qBtd70xYfF7Mi3YRhBcmnAoKpW0jFYn7xjRU-NK3pOpNiB4Wxg782g4_hBXrWmDbBy7v7CP38dPbj9Es5__r5_HQ2L61k06F0zFZ1JSrBOZe2Mq7BTojcsaSGCickkc7xBlsKygkLQnEGdcNrAjWeKsmO0Iet7nqsO3AWwtCbVq9735n-Rkfj9W4k-JVexmstGJ0yLLLA8Z1AH69GSIPufLLQtiZAHJOmWAqlxFSxjL79B72MYx_yeJoSTFmegtEHamla0Hk9Mde1G1E945JKxQUlmSr3UEsIkJuMARqfn3f4N3t4u_ZX-jF0sgfKx0Hn7V7VdzsJmRng97A0Y0r6_PvFLku2rO1jSj0090smWG_Mp7fm09l8emM-fZtzXj_-nfuMv27LAN0CKYfCEvqHlf5f9Q_2bOEh</recordid><startdate>201808</startdate><enddate>201808</enddate><creator>Zhong, Zhenyu</creator><creator>Liang, Shuang</creator><creator>Sanchez-Lopez, Elsa</creator><creator>He, Feng</creator><creator>Shalapour, Shabnam</creator><creator>Lin, Xue-jia</creator><creator>Wong, Jerry</creator><creator>Ding, Siyuan</creator><creator>Seki, Ekihiro</creator><creator>Schnabl, Bernd</creator><creator>Hevener, Andrea L.</creator><creator>Greenberg, Harry B.</creator><creator>Kisseleva, Tatiana</creator><creator>Karin, Michael</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201808</creationdate><title>New mitochondrial DNA synthesis enables NLRP3 inflammasome activation</title><author>Zhong, Zhenyu ; Liang, Shuang ; Sanchez-Lopez, Elsa ; He, Feng ; Shalapour, Shabnam ; Lin, Xue-jia ; Wong, Jerry ; Ding, Siyuan ; Seki, Ekihiro ; Schnabl, Bernd ; Hevener, Andrea L. ; Greenberg, Harry B. ; Kisseleva, Tatiana ; Karin, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c739t-d3c4b46465557c4adf0d6614772a26d6717dd5f0c2e8d6ce6853ebf5b1eb09873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>631/250/256/2177</topic><topic>631/250/262/2106/2517</topic><topic>96/1</topic><topic>96/106</topic><topic>96/109</topic><topic>96/31</topic><topic>96/34</topic><topic>96/44</topic><topic>96/63</topic><topic>96/95</topic><topic>Adapters</topic><topic>Adaptor proteins</topic><topic>Alzheimer's disease</topic><topic>Analysis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biocatalysis</topic><topic>Catalysis</topic><topic>Catalytic activity</topic><topic>Cell activation</topic><topic>Chronic diseases</topic><topic>Chronic illnesses</topic><topic>Cytochrome</topic><topic>Cytological research</topic><topic>Cytosol - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhong, Zhenyu</au><au>Liang, Shuang</au><au>Sanchez-Lopez, Elsa</au><au>He, Feng</au><au>Shalapour, Shabnam</au><au>Lin, Xue-jia</au><au>Wong, Jerry</au><au>Ding, Siyuan</au><au>Seki, Ekihiro</au><au>Schnabl, Bernd</au><au>Hevener, Andrea L.</au><au>Greenberg, Harry B.</au><au>Kisseleva, Tatiana</au><au>Karin, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New mitochondrial DNA synthesis enables NLRP3 inflammasome activation</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2018-08</date><risdate>2018</risdate><volume>560</volume><issue>7717</issue><spage>198</spage><epage>203</epage><pages>198-203</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><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.
New mitochondrial DNA synthesis links the priming and activation of the NLRP3 inflammasome.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30046112</pmid><doi>10.1038/s41586-018-0372-z</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature (London), 2018-08, Vol.560 (7717), p.198-203 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6329306 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 631/250/256/2177 631/250/262/2106/2517 96/1 96/106 96/109 96/31 96/34 96/44 96/63 96/95 Adapters Adaptor proteins Alzheimer's disease Analysis Animals Apoptosis Biocatalysis Catalysis Catalytic activity Cell activation Chronic diseases Chronic illnesses Cytochrome Cytological research Cytosol - metabolism Deoxyribonucleic acid Deoxyribonucleotides Dependence DNA DNA biosynthesis DNA synthesis DNA, Mitochondrial - biosynthesis Enzymes Humanities and Social Sciences Inflammasomes Inflammasomes - metabolism Inflammation Interferon regulatory factor 1 Interferon Regulatory Factor-1 - metabolism Kinases Lipopolysaccharides - pharmacology Macrophages Macrophages - cytology Macrophages - drug effects Mice Mitochondria Mitochondria - metabolism Mitochondria - pathology Mitochondrial DNA multidisciplinary MyD88 protein NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Nucleoside-Phosphate Kinase - genetics Nucleoside-Phosphate Kinase - metabolism Oxidation-Reduction Physiological aspects Receptors Science Science (multidisciplinary) Signal Transduction Synthesis Toll-like receptors Toll-Like Receptors - immunology Transcription Transcription factors Type 2 diabetes |
| title | New mitochondrial DNA synthesis enables NLRP3 inflammasome activation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T06%3A21%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=New%20mitochondrial%20DNA%20synthesis%20enables%20NLRP3%20inflammasome%20activation&rft.jtitle=Nature%20(London)&rft.au=Zhong,%20Zhenyu&rft.date=2018-08&rft.volume=560&rft.issue=7717&rft.spage=198&rft.epage=203&rft.pages=198-203&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-018-0372-z&rft_dat=%3Cgale_pubme%3EA572785621%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2102346532&rft_id=info:pmid/30046112&rft_galeid=A572785621&rfr_iscdi=true |