Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiation

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dc.contributor.authorKeles S.
dc.contributor.authorCharbonnier L.M.
dc.contributor.authorKabaleeswaran V.
dc.contributor.authorReisli I.
dc.contributor.authorGenel F.
dc.contributor.authorGulez N.
dc.contributor.authorAl-Herz W.
dc.contributor.authorRamesh N.
dc.contributor.authorPerez-Atayde A.
dc.contributor.authorKaraca N.E.
dc.contributor.authorKutukculer N.
dc.contributor.authorWu H.
dc.contributor.authorGeha R.S.
dc.contributor.authorChatila T.A.
dc.date.accessioned2019-10-27T08:20:25Z
dc.date.available2019-10-27T08:20:25Z
dc.date.issued2016
dc.departmentEge Üniversitesien_US
dc.description.abstractBackground The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of TH17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear. Objective We sought to elucidate common mechanisms operating in the different forms of HIES. Methods We analyzed the differentiation of CD4+ TH cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. TH cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and TH cell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis. Results There was a profound block in the differentiation of DOCK8-deficient naive CD4+ T cells into TH17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired TH17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity–dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression. Conclusion DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES. © 2016 American Academy of Allergy, Asthma & Immunologyen_US
dc.identifier.doi10.1016/j.jaci.2016.04.023en_US
dc.identifier.endpage1.39E+05en_US
dc.identifier.issn0091-6749
dc.identifier.issue5en_US
dc.identifier.pmid27350570en_US
dc.identifier.scopusqualityN/Aen_US
dc.identifier.startpage1384en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2016.04.023
dc.identifier.urihttps://hdl.handle.net/11454/25643
dc.identifier.volume138en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMosby Inc.en_US
dc.relation.ispartofJournal of Allergy and Clinical Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectCell division cycle 42en_US
dc.subjectdedicator of cytokinesis 8en_US
dc.subjectguanine nucleotide exchange factoren_US
dc.subjecthyper-IgE syndromeen_US
dc.subjectmucocutaneous candidiasisen_US
dc.subjectsignal transducer and activator of transcription 3en_US
dc.subjectsuppressor of cytokine signaling 3en_US
dc.subjectTH17en_US
dc.titleDedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiationen_US
dc.typeArticleen_US

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