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

Erin Janssen, Mira Tohme, Mona Hedayat, Marion Leick, Sudha Kumari, Narayanaswamy Ramesh, Michel J. Massaad, Sumana Ullas, Veronica Azcutia, Christopher C. Goodnow, Katrina L. Randall, Qi Qiao, Hao Wu, Waleed Al-Herz, Dianne Cox, John Hartwig, Darrell J. Irvine, Francis W. Luscinskas, Raif S. Geha

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3837-3851
Number of pages15
JournalJournal of Clinical Investigation
Volume126
Issue number10
DOIs
StatePublished - Oct 3 2016

ASJC Scopus subject areas

  • Medicine(all)

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    Janssen, E., Tohme, M., Hedayat, M., Leick, M., Kumari, S., Ramesh, N., Massaad, M. J., Ullas, S., Azcutia, V., Goodnow, C. C., Randall, K. L., Qiao, Q., Wu, H., Al-Herz, W., Cox, D., Hartwig, J., Irvine, D. J., Luscinskas, F. W., & Geha, R. S. (2016). A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton. Journal of Clinical Investigation, 126(10), 3837-3851. https://doi.org/10.1172/JCI85774