WASp verprolin homology, cofilin homology, and acidic region domain-mediated actin polymerization is required for T cell development.
All members of the Wiskott-Aldrich syndrome protein (WASp) family contain a carboxyl-terminal verprolin homology, cofilin homology, and acidic region (VCA) domain that binds and activates the Arp2/3 complex, thereby linking these proteins to the induction of actin polymerization. Although the VCA domain imbues WASp and other WASp family members with the capacity to modulate cytoskeletal organization, little is known about the impact of this domain activity on lymphoid cell function. Here we demonstrate that T cell-restricted expression of VCA domain-deleted WASp (WASpdeltaVCA) in WAS(-/-) mice engenders a severe early block in T lymphopoiesis associated with impaired T cell antigen receptor alphabeta expression and a consequent failure to generate single-positive CD4(+) and CD8(+) T cells. These latter defects, which are not observed in WAS(-/-) mice, are associated with impaired induction of cellular actin polymerization and a failure in the terminal differentiation of double-negative thymocytes. These findings indicate that WASp family proteins play an essential role in modulating the signaling events required for early thymocyte development and reveal their capacity to subserve this role to depend on VCA domain-mediated actin polymerization.
Zhang
Jinyi
J
Department of Medicine, University of Toronto, Toronto, ON, Canada M5G 1X5.
Shi
Fabio
F
Badour
Karen
K
Deng
Yupu
Y
McGavin
Mary K H
MK
Siminovitch
Katherine A
KA
D051339:Actin Depolymerizing Factors; D000199:Actins / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D002454:Cell Differentiation; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D005434:Flow Cytometry; D005656:Fungal Proteins / Q000737:chemistry*; D017353:Gene Deletion; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000737:chemistry*; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D019076:Transgenes; D051316:Wiskott-Aldrich Syndrome Protein
D051339:Actin Depolymerizing Factors; D000199:Actins; D017252:CD3 Complex; D018076:DNA, Complementary; D005656:Fungal Proteins; D018960:Hyaluronan Receptors; D008840:Microfilament Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D029701:Saccharomyces cerevisiae Proteins; C090350:VRP1 protein, S cerevisiae; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein