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dc.contributor.authorCader, Mohammeden
dc.contributor.authorBoroviak, Katharinaen
dc.contributor.authorZhang, Qifengen
dc.contributor.authorAssadi, Ghazalehen
dc.contributor.authorKempster, Sarah Len
dc.contributor.authorSewell, Gavin Williamen
dc.contributor.authorSaveljeva, Svetlanaen
dc.contributor.authorAshcroft, Jonathan Wen
dc.contributor.authorClare, Simonen
dc.contributor.authorMukhopadhyay, Subhankaren
dc.contributor.authorBrown, Karen Pen
dc.contributor.authorTschurtschenthaler, Markusen
dc.contributor.authorRaine, Timen
dc.contributor.authorDoe, Brendanen
dc.contributor.authorChilvers, Edwinen
dc.contributor.authorGriffin, Julianen
dc.contributor.authorKaneider, Nicole Cen
dc.contributor.authorFloto, Andresen
dc.contributor.authorD’Amato, Mauroen
dc.contributor.authorBradley, Allanen
dc.contributor.authorWakelam, Michaelen
dc.contributor.authorDougan, Gordonen
dc.contributor.authorKaser, Arthuren
dc.date.accessioned2016-08-15T17:19:15Z
dc.date.available2016-08-15T17:19:15Z
dc.date.issued2016-08-01en
dc.identifier.issn1529-2908
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/257280
dc.description.abstractSingle-nucleotide variations in $\small \textit{C13orf31 (LACC1)}$ that encode p.C284R and p.I254V in a protein of unknown function (called ‘FAMIN’ here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn’s disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.
dc.description.sponsorshipSupported by the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement 260961, the Wellcome Trust (investigator award 106260/Z/14/Z; a PhD fellowship for clinicians; and a Career Re-Entry Fellowship), the Wellcome Trust Sanger Institute, the US National Institutes of Health (5U420D011174 and 5U54HG006348), the Biotechnology and Biological Sciences Research Council, the National Institute for Health Research Cambridge Biomedical Research Centre, the European Crohn’s and Colitis Organisation and the Swedish Medical Research Council and the Olle Engkvist foundation.
dc.languageEnglishen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.subjectcell biologyen
dc.subjectimmunologyen
dc.titleC13orf31 (FAMIN) is a central regulator of immunometabolic functionen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ni.3532en
prism.publicationDate2016en
prism.publicationNameNature Immunologyen
dc.identifier.doi10.17863/CAM.1210
dcterms.dateAccepted2016-07-01en
rioxxterms.versionofrecord10.1038/ni.3532en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-08-01en
dc.contributor.orcidCader, Mohammed [0000-0002-4121-748X]
dc.contributor.orcidChilvers, Edwin [0000-0002-4230-9677]
dc.contributor.orcidGriffin, Julian [0000-0003-1336-7744]
dc.contributor.orcidFloto, Andres [0000-0002-2188-5659]
dc.contributor.orcidBradley, Allan [0000-0002-2349-8839]
dc.contributor.orcidWakelam, Michael [0000-0003-4059-9276]
dc.contributor.orcidDougan, Gordon [0000-0003-0022-965X]
dc.identifier.eissn1529-2916
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/P011705/1)
pubs.funder-project-idWellcome Trust (103077/Z/13/Z)
pubs.funder-project-idWELLCOME TRUST (106260/Z/14/Z)
pubs.funder-project-idEuropean Research Council (260961)
pubs.funder-project-idWellcome Trust (100891/Z/13/Z)
pubs.funder-project-idWellcome Trust (100675/Z/12/Z)
rioxxterms.freetoread.startdate2017-02-01


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