[HTML][HTML] A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton

E Janssen, M Tohme, M Hedayat… - The Journal of …, 2016 - Am Soc Clin Investig
E Janssen, M Tohme, M Hedayat, M Leick, S Kumari, N Ramesh, MJ Massaad, S Ullas…
The Journal of clinical investigation, 2016Am Soc Clin Investig
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 WASp-interacting protein (WIP) bridges …
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 WASp-interacting 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.
The Journal of Clinical Investigation