NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain
NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transc...
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| Veröffentlicht in: | The Journal of experimental medicine 2017-06, Vol.214 (6), p.1725-1736 |
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| container_title | The Journal of experimental medicine |
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| creator | Stutz, Andrea Kolbe, Carl-Christian Stahl, Rainer Horvath, Gabor L Franklin, Bernardo S van Ray, Olivia Brinkschulte, Rebecca Geyer, Matthias Meissner, Felix Latz, Eicke |
| description | NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge-charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation. |
| doi_str_mv | 10.1084/jem.20160933 |
| format | Article |
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Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge-charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20160933</identifier><identifier>PMID: 28465465</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Aberration ; Adapters ; Amino Acid Sequence ; Animals ; Assembly ; Caspase ; Caspase-1 ; Cell activation ; Cell death ; Cytokines ; Dephosphorylation ; Hazards ; HEK293 Cells ; Humans ; Immune response ; Inflammasomes ; Inflammasomes - metabolism ; Inflammation ; Kinases ; Mice ; Models, Biological ; Models, Molecular ; NLR Family, Pyrin Domain-Containing 3 Protein - chemistry ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; Pattern recognition ; Pattern recognition receptors ; Phosphorylation ; Phosphoserine - metabolism ; Protein Binding ; Protein Domains ; Protein Phosphatase 2 - metabolism ; Pyrin - chemistry ; Pyrin protein ; Structure-Activity Relationship ; Transcription activation</subject><ispartof>The Journal of experimental medicine, 2017-06, Vol.214 (6), p.1725-1736</ispartof><rights>2017 Stutz et al.</rights><rights>Copyright Rockefeller University Press Jun 5, 2017</rights><rights>2017 Stutz et al. 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-b5ee84c0f13440ebbacf2a85174b13bfaff31ee7e264984e6f351d63ecf5fd523</citedby><cites>FETCH-LOGICAL-c511t-b5ee84c0f13440ebbacf2a85174b13bfaff31ee7e264984e6f351d63ecf5fd523</cites><orcidid>0000-0002-8702-7278 ; 0000-0002-7896-8703 ; 0000-0003-0309-595X ; 0000-0003-1488-5666 ; 0000-0003-1000-7989 ; 0000-0002-1449-0018</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28465465$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stutz, Andrea</creatorcontrib><creatorcontrib>Kolbe, Carl-Christian</creatorcontrib><creatorcontrib>Stahl, Rainer</creatorcontrib><creatorcontrib>Horvath, Gabor L</creatorcontrib><creatorcontrib>Franklin, Bernardo S</creatorcontrib><creatorcontrib>van Ray, Olivia</creatorcontrib><creatorcontrib>Brinkschulte, Rebecca</creatorcontrib><creatorcontrib>Geyer, Matthias</creatorcontrib><creatorcontrib>Meissner, Felix</creatorcontrib><creatorcontrib>Latz, Eicke</creatorcontrib><title>NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge-charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation.</description><subject>Aberration</subject><subject>Adapters</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Assembly</subject><subject>Caspase</subject><subject>Caspase-1</subject><subject>Cell activation</subject><subject>Cell death</subject><subject>Cytokines</subject><subject>Dephosphorylation</subject><subject>Hazards</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immune response</subject><subject>Inflammasomes</subject><subject>Inflammasomes - metabolism</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Models, Molecular</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - chemistry</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</subject><subject>Pattern recognition</subject><subject>Pattern recognition receptors</subject><subject>Phosphorylation</subject><subject>Phosphoserine - metabolism</subject><subject>Protein Binding</subject><subject>Protein Domains</subject><subject>Protein Phosphatase 2 - metabolism</subject><subject>Pyrin - chemistry</subject><subject>Pyrin protein</subject><subject>Structure-Activity Relationship</subject><subject>Transcription activation</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9rFTEQx4Mo9rV68ywBLz24bWbzY7MXQUqtwqMV0XPI7k768thsnsmusP-9Kf2BehFmGJj58GVmvoS8AXYGTIvzPYazmoFiLefPyAakYFUruX5ONozVdQWMNUfkOOc9YyCEVC_JUa2FkiU25OZ6--0rp35yow3B5hiQ2pwxdONKfaYJb5fRzjjQbqWHXcwl01o6Pk40OjrvkB7W5Cc6xGD99Iq8cHbM-PqhnpAfny6_X3yutjdXXy4-bqteAsxVJxG16JkDLgTDrrO9q62W0IgOeOescxwQG6yVaLVA5biEQXHsnXSDrPkJ-XCve1i6gEOP05zsaA7JB5tWE603f08mvzO38ZcpZ7O2VUXg9EEgxZ8L5tkEn3scRzthXLKBFkCBbhr-f1S3ogUlFSvou3_QfVzSVD5RBDUXXCl-t_z7e6pPMeeE7mlvYObOVFNMNY-mFvztn7c-wY8u8t8KIp4P</recordid><startdate>20170605</startdate><enddate>20170605</enddate><creator>Stutz, Andrea</creator><creator>Kolbe, Carl-Christian</creator><creator>Stahl, Rainer</creator><creator>Horvath, Gabor L</creator><creator>Franklin, Bernardo S</creator><creator>van Ray, Olivia</creator><creator>Brinkschulte, Rebecca</creator><creator>Geyer, Matthias</creator><creator>Meissner, Felix</creator><creator>Latz, Eicke</creator><general>Rockefeller University Press</general><general>The Rockefeller University Press</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>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8702-7278</orcidid><orcidid>https://orcid.org/0000-0002-7896-8703</orcidid><orcidid>https://orcid.org/0000-0003-0309-595X</orcidid><orcidid>https://orcid.org/0000-0003-1488-5666</orcidid><orcidid>https://orcid.org/0000-0003-1000-7989</orcidid><orcidid>https://orcid.org/0000-0002-1449-0018</orcidid></search><sort><creationdate>20170605</creationdate><title>NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain</title><author>Stutz, Andrea ; 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Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge-charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>28465465</pmid><doi>10.1084/jem.20160933</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-8702-7278</orcidid><orcidid>https://orcid.org/0000-0002-7896-8703</orcidid><orcidid>https://orcid.org/0000-0003-0309-595X</orcidid><orcidid>https://orcid.org/0000-0003-1488-5666</orcidid><orcidid>https://orcid.org/0000-0003-1000-7989</orcidid><orcidid>https://orcid.org/0000-0002-1449-0018</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aberration Adapters Amino Acid Sequence Animals Assembly Caspase Caspase-1 Cell activation Cell death Cytokines Dephosphorylation Hazards HEK293 Cells Humans Immune response Inflammasomes Inflammasomes - metabolism Inflammation Kinases Mice Models, Biological Models, Molecular NLR Family, Pyrin Domain-Containing 3 Protein - chemistry NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Pattern recognition Pattern recognition receptors Phosphorylation Phosphoserine - metabolism Protein Binding Protein Domains Protein Phosphatase 2 - metabolism Pyrin - chemistry Pyrin protein Structure-Activity Relationship Transcription activation |
| title | NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain |
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