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 Mills, Katherine A. Siminovitch

Research output: Contribution to journalArticle

69 Citations (Scopus)

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

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Sorting Nexins
Wiskott-Aldrich Syndrome Protein
Protein Transport
Endocytosis
T-Lymphocytes
Clathrin
Actins
T-Cell Antigen Receptor
Phosphotransferases
Transport Vesicles
src Homology Domains
Polymerization
Ligation
Signal Transduction

Keywords

  • Actin cytoskeleton
  • Costimulation
  • Lymphocyte activation
  • Signaling

ASJC Scopus subject areas

  • General

Cite this

Interaction of the Wiskott-Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignalling in T cells. / Badour, Karen; McGavin, Mary K.H.; Zhang, Jinyi; Freeman, Spencer; Vieira, Claudia; Filipp, Dominik; Julius, Michael; Mills, Gordon; Siminovitch, Katherine A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 5, 30.01.2007, p. 1593-1598.

Research output: Contribution to journalArticle

Badour, Karen ; McGavin, Mary K.H. ; Zhang, Jinyi ; Freeman, Spencer ; Vieira, Claudia ; Filipp, Dominik ; Julius, Michael ; Mills, Gordon ; Siminovitch, Katherine A. / Interaction of the Wiskott-Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignalling in T cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 5. pp. 1593-1598.
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AU - Vieira, Claudia

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