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dc.contributor.authorKeane, Josephen
dc.contributor.authorO'Sullivan, Maryen
dc.contributor.authorO'Neill, Lukeen
dc.contributor.authorLavelle, Edwarden
dc.contributor.authorCorr, Sineaden
dc.contributor.authorPalsson Mcdermott, Evaen
dc.contributor.authorSheedy, Fredericken
dc.contributor.authorNi Cheallaigh, Clionaen
dc.contributor.authorGleeson, Lauraen
dc.contributor.authorMunoz-Wolf, Nataliaen
dc.date.accessioned2016-09-27T14:17:00Z
dc.date.available2016-09-27T14:17:00Z
dc.date.issued2016en
dc.date.submitted2016en
dc.identifier.citationN? Cheallaigh, C., Sheedy, F.J., Harris, J., Mu?oz-Wolf, N., Lee, J., West, K., McDermott, E.P., Smyth, A., Gleeson, L.E., Coleman, M., Martinez, N., Hearnden, C.H., Tynan, G.A., Carroll, E.C., Jones, S.A., Corr, S.C., Bernard, N.J., Hughes, M.M., Corcoran, S.E., O'Sullivan, M., Fallon, C.M., Kornfeld, H., Golenbock, D., Gordon, S.V., O'Neill, L.A., Keane, J. Lavelle, E.C, A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling., Immunity, 44, 2, 2016, 368 - 379en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/77444
dc.descriptionPUBLISHEDen
dc.description.abstractHumans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.en
dc.description.sponsorshipSupported in part by Health Research Board Ireland by grant NSAFP 2009/2 (C.N.C.), CSA/2004/7 and CSA/2012/16 (J.K.), The Royal City of Dublin Hospital Trust (J.K.), NIH grant HL081149 (H.K.), Wellcome Trust PhD award 102395/Z/13/Z (A.S.), Science Foundation Ireland Investigator Awards 08/IN.1/B2038 (S.G.) and 12/IA/1421 (E.C.L.), and the Science Foundation Ireland Strategic Research Cluster 07/SRC/B1144 (E.C.L.).en
dc.format.extent368en
dc.format.extent379en
dc.language.isoenen
dc.relation.ispartofseriesImmunityen
dc.relation.ispartofseries44en
dc.relation.ispartofseries2en
dc.rightsYen
dc.subjectcommon S180L polymorphismen
dc.subject.lcshcommon S180L polymorphismen
dc.titleA Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling.en
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/josephmken
dc.identifier.peoplefinderurlhttp://people.tcd.ie/osullim2en
dc.identifier.peoplefinderurlhttp://people.tcd.ie/lgleesonen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/fsheedyen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/laoneillen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/lavelleeen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/nicheac2en
dc.identifier.peoplefinderurlhttp://people.tcd.ie/palssoneen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/corrscen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/munozwonen
dc.identifier.rssinternalid112500en
dc.rights.ecaccessrightsopenAccess
dc.contributor.sponsorGrantNumber07/SRC/B1144en
dc.contributor.sponsorGrantNumber08/IN.1/B2038en
dc.contributor.sponsorGrantNumber12/IA/1421en
dc.subject.TCDThemeImmunology, Inflammation & Infectionen
dc.identifier.rssurihttp://www.sciencedirect.com/science/article/pii/S1074761316300061en
dc.identifier.orcid_id0000-0001-5313-385Xen


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