DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

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dc.contributor.authorJabara, Haifa H.
dc.contributor.authorMcDonald, Douglas R.
dc.contributor.authorJanssen, Erin
dc.contributor.authorMassaad, Michel J.
dc.contributor.authorRamesh, Narayanaswamy
dc.contributor.authorBorzutzky, Arturo
dc.contributor.authorRauter, Ingrid
dc.date.accessioned2020-03-26T18:24:53Z
dc.date.available2020-03-26T18:24:53Z
dc.date.issued2012
dc.departmentSelçuk Üniversitesien_US
dc.description.abstractThe adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27(+) memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-kappa B, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.en_US
dc.description.sponsorshipUS Public Health ServiceUnited States Public Health Service [P01AI076210, T32AI007512, R01AI083503, R21AI087627, K08AI076625]; Dubai Harvard Foundation for Medical Research; Swiss National Science FoundationSwiss National Science Foundation (SNSF) [PASMP3-127678/1]; Clinical Immunology Society; Manton Foundationen_US
dc.description.sponsorshipWe thank F. Uckun (University of Southern California, Los Angeles) for SYKINH-61; R. Treisman (Cancer Research UK) for hemagglutinin-tagged MRTF-A;J.-L. Casanova (The Rockefeller University), A. Puel and C. Picard (Hopital Necker-Enfants Malades, France) for the MyD88-deficient EBV-B cell line; K. Eurich for technical assistance; A. Rambhatla and A. Chen for help in DNA sequencing; members of the Geha laboratory for discussions; J. Kagan and H. Oettgen for comments on the manuscript; and the patients and their families for donating blood. Supported by the US Public Health Service (P01AI076210, T32AI007512 and R01AI083503 to R. S. G.; R21AI087627 to T. A. C.; and K08AI076625 to D. R. M.), the Dubai Harvard Foundation for Medical Research (R. S. G. and L.D.N.), the Swiss National Science Foundation (PASMP3-127678/1 to M. R.), the Clinical Immunology Society (E.J.) and the Manton Foundation (E.J. and L.D.N.).en_US
dc.identifier.doi10.1038/ni.2305en_US
dc.identifier.endpage+en_US
dc.identifier.issn1529-2908en_US
dc.identifier.issue6en_US
dc.identifier.pmid22581261en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage612en_US
dc.identifier.urihttps://dx.doi.org/10.1038/ni.2305
dc.identifier.urihttps://hdl.handle.net/20.500.12395/27923
dc.identifier.volume13en_US
dc.identifier.wosWOS:000304203900016en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherNATURE PUBLISHING GROUPen_US
dc.relation.ispartofNATURE IMMUNOLOGYen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.selcuk20240510_oaigen_US
dc.titleDOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activationen_US
dc.typeArticleen_US

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