TY - JOUR
T1 - A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton
AU - Janssen, Erin
AU - Tohme, Mira
AU - Hedayat, Mona
AU - Leick, Marion
AU - Kumari, Sudha
AU - Ramesh, Narayanaswamy
AU - Massaad, Michel J.
AU - Ullas, Sumana
AU - Azcutia, Veronica
AU - Goodnow, Christopher C.
AU - Randall, Katrina L.
AU - Qiao, Qi
AU - Wu, Hao
AU - Al-Herz, Waleed
AU - Cox, Dianne
AU - Hartwig, John
AU - Irvine, Darrell J.
AU - Luscinskas, Francis W.
AU - Geha, Raif S.
PY - 2016/10/3
Y1 - 2016/10/3
N2 - Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role in the initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype of WAS includes susceptibility to infection, allergy, autoimmunity, and malignancy and overlaps with the symptoms of dedicator of cytokinesis 8 (DOCK8) deficiency, suggesting that the 2 syndromes share common pathogenic mechanisms. Here, we demonstrated that the WASpinteracting protein (WIP) bridges DOCK8 to WASp and actin in T cells. We determined that the guanine nucleotide exchange factor activity of DOCK8 is essential for the integrity of the subcortical actin cytoskeleton as well as for TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes, all of which also depend on WASp. These results indicate that DOCK8 and WASp are in the same signaling pathway that links TCRs to the actin cytoskeleton in TCR-driven actin assembly. Further, they provide an explanation for similarities in the clinical phenotypes of WAS and DOCK8 deficiency.
AB - Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role in the initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype of WAS includes susceptibility to infection, allergy, autoimmunity, and malignancy and overlaps with the symptoms of dedicator of cytokinesis 8 (DOCK8) deficiency, suggesting that the 2 syndromes share common pathogenic mechanisms. Here, we demonstrated that the WASpinteracting protein (WIP) bridges DOCK8 to WASp and actin in T cells. We determined that the guanine nucleotide exchange factor activity of DOCK8 is essential for the integrity of the subcortical actin cytoskeleton as well as for TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes, all of which also depend on WASp. These results indicate that DOCK8 and WASp are in the same signaling pathway that links TCRs to the actin cytoskeleton in TCR-driven actin assembly. Further, they provide an explanation for similarities in the clinical phenotypes of WAS and DOCK8 deficiency.
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U2 - 10.1172/JCI85774
DO - 10.1172/JCI85774
M3 - Article
C2 - 27599296
AN - SCOPUS:84991628476
SN - 0021-9738
VL - 126
SP - 3837
EP - 3851
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -