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MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism

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cam.issuedOnline2017-06-28
dc.contributor.authorLi, X
dc.contributor.authorThome, S
dc.contributor.authorMa, X
dc.contributor.authorAmrute-Nayak, M
dc.contributor.authorFinigan, A
dc.contributor.authorKitt, L
dc.contributor.authorMasters, L
dc.contributor.authorJames, JR
dc.contributor.authorShi, Y
dc.contributor.authorMeng, G
dc.contributor.authorMallat, Z
dc.contributor.orcidLi, Xuan [0000-0002-0754-3011]
dc.contributor.orcidJames, John [0000-0003-1452-7578]
dc.contributor.orcidMallat, Ziad [0000-0003-0443-7878]
dc.date.accessioned2017-08-14T13:00:46Z
dc.date.available2017-08-14T13:00:46Z
dc.date.issued2017-06-28
dc.description.abstractExcessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in many chronic inflammatory diseases, including cardiovascular and Alzheimer's disease. Here we show that microtubule-affinity regulating kinase 4 (MARK4) binds to NLRP3 and drives it to the microtubule-organizing centre, enabling the formation of one large inflammasome speck complex within a single cell. MARK4 knockdown or knockout, or disruption of MARK4-NLRP3 interaction, impairs NLRP3 spatial arrangement and limits inflammasome activation. Our results demonstrate how an evolutionarily conserved protein involved in the regulation of microtubule dynamics orchestrates NLRP3 inflammasome activation by controlling its transport to optimal activation sites, and identify a targetable function for MARK4 in the control of innate immunity.
dc.description.sponsorshipThe work was supported by NNSFC grant (81370620 to G.M.), BHF grant (CH/10/001/27642 to Z.M.), ERC grant (2891164 to Z.M.), and BHF fellowship grant (FS/14/28/30713 to X.L.).
dc.identifier.doi10.17863/CAM.12594
dc.identifier.eissn2041-1723
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266349
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Nature
dc.publisher.urlhttp://dx.doi.org/10.1038/ncomms15986
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectHumans
dc.subjectInflammasomes
dc.subjectInterleukin-1beta
dc.subjectMacrophages
dc.subjectMale
dc.subjectMice
dc.subjectMicrotubule-Organizing Center
dc.subjectMicrotubules
dc.subjectNLR Family, Pyrin Domain-Containing 3 Protein
dc.subjectPrimary Cell Culture
dc.subjectProtein Serine-Threonine Kinases
dc.titleMARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism
dc.typeArticle
dcterms.dateAccepted2017-05-17
prism.number15986
prism.publicationDate2017
prism.publicationNameNature Communications
prism.volume8
pubs.funder-project-idWellcome Trust (099966/Z/12/Z)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (CH/10/001/27642)
rioxxterms.licenseref.startdate2017-06-28
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/ncomms15986

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