Published in
Nature Research, Nature Immunology, 6(13), p. 612-620, 2012
DOI: 10.1038/ni.2305
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DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation
,
Michel J. Massaad ,
Narayanaswamy Ramesh,
Arturo Borzutzky,
Ingrid Rauter,
Halli Benson,
Lynda Schneider,
Mike Recher,
Sachin Baxi,
Rima Wakim,
Luigi D. Notarangelo,
Ghassan Dbaibo,
Majed Dasouki
and other authors.
Full text: Download
Abstract
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-kappaB, 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.