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

Jabara, Haifa H; McDonald, Douglas R; Janssen, Erin; Massaad, Michel J; Ramesh, Narayanaswamy; Borzutzky, Arturo; Rauter, Ingrid; Benson, Halli; Schneider, Lynda; Baxi, Sachin; Recher, Mike; Notarangelo, Luigi D; Wakim, Rima; Dbaibo, Ghassan; Dasouki, Majed; Al-Herz, Waleed; Barlan, Isil; Baris, Safa; Kutukculer, Necil; Ochs, Hans D; Plebani, Alessandro; Kanariou, Maria; Lefranc, Gerard; Reisli, Ismail; Fitzgerald, Katherine A; Golenbock, Douglas; Manis, John; Keles, Sevgi; Ceja, Reuben; Chatila, Talal A; Geha, Raif S.
Nat Immunol; 13(6): 612-20, 2012 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-22581261
The 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-κB, 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.
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