A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton.
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.
Erin
E
Janssen
Mira
M
Tohme
Mona
M
Hedayat
Marion
M
Leick
Sudha
S
Kumari
Narayanaswamy
N
Ramesh
Michel J
MJ
Massaad
Sumana
S
Ullas
Veronica
V
Azcutia
Christopher C
CC
Goodnow
Katrina L
KL
Randall
Qi
Q
Qiao
Hao
H
Wu
Waleed
W
Al-Herz
Dianne
D
Cox
John
J
Hartwig
Darrell J
DJ
Irvine
Francis W
FW
Luscinskas
Raif S
RS
Geha
D008841:Actin Cytoskeleton / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement; D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D040542:Mechanotransduction, Cellular; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D060066:Protein Interaction Maps; D055503:Protein Multimerization; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C505592:NEDD9 protein, mouse; D011948:Receptors, Antigen, T-Cell; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein