Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression.
CTLA-4 is a lymphocyte cell surface receptor expressed by activated T cells that functions to down-regulate T cell responses induced by TCR and CD28 stimulation. Since CTLA-4 competes with CD28 for binding to the common ligands B7-1 and B7-2, the level of CTLA-4 surface expression is likely to play an ... important role in its ability to inhibit CD28-dependent T cell activation. The factors that regulate these levels are poorly understood. Recent studies have revealed that following T cell activation, the majority of CTLA-4 is localized intracellularly rather than on the cell surface, and surface CTLA-4 is rapidly reinternalized. In this study, we investigate the molecular mechanism underlying the rapid clearance of CTLA-4 from the cell surface. The data demonstrate that cell surface CTLA-4 is endocytosed into clathrin-coated vesicles even in the absence of ligand. The targeting of CTLA-4 to clathrin-coated vesicles is mediated by the clathrin-associated adaptor complex AP-2. The cytoplasmic domain of CTLA-4 was found to specifically bind to AP50, the medium chain subunit of AP-2 in both yeast two-hybrid and coimmunoprecipitation assays. The interaction requires the peptide sequence 199-GVYVKM-204 in the cytoplasmic tail of CTLA-4. Mutation of the CTLA-4 amino acid residue Y201 abrogates the interaction with AP50, resulting in the accumulation of CTLA-4 at the cell surface. Together these data suggest that the interaction of CTLA-4 with AP50 plays an important role in regulating the cell surface expression of CTLA-4.
Mesh Terms:
Adaptor Protein Complex 2, Adaptor Protein Complex mu Subunits, Adaptor Proteins, Vesicular Transport, Amino Acid Sequence, Antigens, CD, Antigens, Differentiation, Endocytosis, Humans, Immunoconjugates, Jurkat Cells, Lymphocyte Activation, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Phosphoproteins, Receptor Aggregation, Signal Transduction, T-Lymphocytes
Adaptor Protein Complex 2, Adaptor Protein Complex mu Subunits, Adaptor Proteins, Vesicular Transport, Amino Acid Sequence, Antigens, CD, Antigens, Differentiation, Endocytosis, Humans, Immunoconjugates, Jurkat Cells, Lymphocyte Activation, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Phosphoproteins, Receptor Aggregation, Signal Transduction, T-Lymphocytes
J. Immunol.
Date: Jul. 01, 1997
PubMed ID: 9200449
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