title: NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component.
abstract: The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1β (IL-1β) and IL-18. We found here that activation of the NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS). This interaction was necessary for the formation of a complex containing NLRP3 and the adaptor ASC, oligomerization of ASC and activation of caspase-1. NEK7 promoted the NLRP3-dependent cellular inflammatory response to intraperitoneal challenge with monosodium urate and the development of experimental autoimmune encephalitis in mice. Our findings suggest that NEK7 serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division.
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Hexin
authors.initials: H
authors.lastname: Shi
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Tang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Maggy
authors.initials: M
authors.lastname: Fina
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lijing
authors.initials: L
authors.lastname: Su
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pratt
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chun Hui
authors.initials: CH
authors.lastname: Bu
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Hildebrand
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lyon
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Scott
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jiexia
authors.initials: J
authors.lastname: Quan
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Russell
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Arnett
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Jurek
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kravchenko
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Mathison
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Eva Marie Y
authors.initials: EM
authors.lastname: Moresco
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Monson
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ulevitch
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1; D002850:Chromatography, Gel; D003114:Colony-Forming Units Assay; D016207:Cytokines; D003598:Cytoskeletal Proteins; D003713:Dendritic Cells; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008938:Mitosis / Q000276:immunology*; D009000:Monocytes; D000072379:NIMA-Related Kinases; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species; D013116:Spinal Cord / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C402202:PYCARD protein, human; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; C512685:NEK7 protein, human; D000072379:NIMA-Related Kinases; C512686:Nek7 protein, mouse; D017346:Protein Serine-Threonine Kinases; D020170:Caspase 1