Ubiquitylation-dependent negative regulation of WASp is essential for actin cytoskeleton dynamics.
The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of actin dynamics during cell motility and adhesion, and mutations in its gene are responsible for Wiskott-Aldrich syndrome (WAS). Here, we demonstrate that WASp is ubiquitylated following T-cell antigen receptor (TCR) activation. WASp phosphorylation at tyrosine 291 results in recruitment of the E3 ligase Cbl-b, which, together with c-Cbl, carries out WASp ubiquitylation. Lysine residues 76 and 81, located at the WASp WH1 domain, which contains the vast majority of WASp gene mutations, serve as the ubiquitylation sites. Disruption of WASp ubiquitylation causes WASp accumulation and alters actin dynamics and the formation of actin-dependent structures. Our data suggest that regulated degradation of activated WASp might be an efficient strategy by which the duration and localization of actin rearrangement and the intensity of T-cell activation are controlled.
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Barak
B
Reicher
Noah
N
Joseph
Ahuvit
A
David
Maor H
MH
Pauker
Orly
O
Perl
Mira
M
Barda-Saad
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D054875:Ubiquitination; D051316:Wiskott-Aldrich Syndrome Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human