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

doi:10.1172/JCI85774

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

89 Citations (Scopus)

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 language	English
Pages (from-to)	3837-3851
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	126
Issue number	10
DOIs	https://doi.org/10.1172/JCI85774
Publication status	Published - 3 Oct 2016

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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

@article{77ef27587df946c8a4e2f16e1a2e6e5e,

title = "A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton",

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.",

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

year = "2016",

month = oct,

day = "3",

doi = "10.1172/JCI85774",

language = "English",

volume = "126",

pages = "3837--3851",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

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Janssen, E, Tohme, M, Hedayat, M, Leick, M, Kumari, S, Ramesh, N, Massaad, MJ, Ullas, S, Azcutia, V, Goodnow, CC, Randall, KL, Qiao, Q, Wu, H, Al-Herz, W, Cox, D, Hartwig, J, Irvine, DJ, Luscinskas, FW & Geha, RS 2016, 'A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton', Journal of Clinical Investigation, vol. 126, no. 10, pp. 3837-3851. https://doi.org/10.1172/JCI85774

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.

UR - http://www.scopus.com/inward/record.url?scp=84991628476&partnerID=8YFLogxK

U2 - 10.1172/JCI85774

DO - 10.1172/JCI85774

M3 - Article

SN - 0021-9738

VL - 126

SP - 3837

EP - 3851

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 10

ER -

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

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