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, Sevgi
dc.contributor.authorCharbonnier, Louis Marie
dc.contributor.authorKabaleeswaran, Venkataraman
dc.contributor.authorReisli, Ismail
dc.contributor.authorGenel, Ferah
dc.contributor.authorGulez, Nesrin
dc.contributor.authorAl-Herz, Waleed
dc.date.accessioned2024-02-23T14:12:29Z
dc.date.available2024-02-23T14:12:29Z
dc.date.issued2016
dc.departmentNEÜen_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 T(H)17 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(+) T-H cell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. T-H cell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and T-H 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 T(H)17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired T(H)17 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.en_US
dc.description.sponsorshipNational Institutes of Health [5R01AI065617]; Scientific and Technological Research Council of Turkey [1059B191300622]en_US
dc.description.sponsorshipSupported by the National Institutes of Health (5R01AI065617, to T.A.C.) and a grant from the Scientific and Technological Research Council of Turkey (1059B191300622 to S.K.).en_US
dc.identifier.doi10.1016/j.jaci.2016.04.023
dc.identifier.endpage+en_US
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.issue5en_US
dc.identifier.pmid27350570en_US
dc.identifier.scopus2-s2.0-84977487188en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1384en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2016.04.023
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12078
dc.identifier.volume138en_US
dc.identifier.wosWOS:000389542700018en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMosby-Elsevieren_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/openAccessen_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.subjectSuppressor Of Cytokine Signaling 3en_US
dc.subjectSignal Transducer And Activator Of Transcription 3en_US
dc.subjectT(H)17en_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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