Interaction of the Wiskott-Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignalling in T cells

Karen Badour, Mary K.H. McGavin, Jinyi Zhang, Spencer Freeman, Claudia Vieira, Dominik Filipp, Michael Julius, Gordon B. Mills, Katherine A. Siminovitch

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

The Wiskott-Aldrich syndrome protein (WASp) plays a major role in coupling T cell antigen receptor (TCR) stimulation to induction of actin cytoskeletal changes required for T cell activation. Here, we report that WASp inducibly binds the sorting nexin 9 (SWX9) in T cells and that WASp, SNX9, p85, and CD28 colocalize within clathrin-containing endocytic vesicles after TCR/CD28 costimulation. SNX9, implicated in clathrin-mediated endocytosis, binds WASp via its SH3 domain and uses its PX domain to interact with the phosphoinositol 3-kinase regulatory subunit p85 and product, phosphoinositol (3,4,5)P 3. The data reveal ligation-induced CD28 endocytosis to be clathrin- and phosphoinositol 3-kinase-dependent and TCR/CD28-evoked CD28 internalization and NFAT activation to be markedly enhanced by SNX9 overexpression, but severely impaired by expression of an SNX9 mutant (SNX9ΔPX) lacking p85-binding capacity. CD28 endocytosis and CD28-evoked actin polymerization also are impaired in WASp-deficient T cells. These findings suggest that SNX9 couples WASp to p85 and CD28 so as to link CD28 engagement to its internalization and to WASp-mediated actin remodeling required for CD28 cosignaling. Thus, the WASp/SNX9/p85/CD28 complex enables a unique interface of endocytic, actin polymerizing, and signal transduction pathways required for CD28-mediated T cell costimulation.

Original languageEnglish (US)
Pages (from-to)1593-1598
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number5
DOIs
StatePublished - Jan 30 2007
Externally publishedYes

Keywords

  • Actin cytoskeleton
  • Costimulation
  • Lymphocyte activation
  • Signaling

ASJC Scopus subject areas

  • General

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