Abstract
Fas ligand (FasL) triggers apoptosis during cytotoxicity mediated by cytotoxic T lymphocytes and during immune downregulation. The ability of T cells and natural killer cells to trigger apoptosis through this mechanism is controlled by the cell surface expression of FasL (ref. 2). Because FasL expression is up-regulated on activation, FasL was thought to be delivered directly to the cell surface. Here we show that newly synthesized FasL is stored in specialized secretory lysosomes in both CD4+ and CD8+ T cells and natural killer cells, and that polarized degranulation controls the delivery of FasL to the cell surface. In this way, FasL-mediated apoptosis is finely controlled by receptor-mediated target-cell recognition. The cytoplasmic tail of FasL contains signals that sort FasL to secretory lysosomes in hemopoietic cells. This pathway may provide a general mechanism for controlling the cell surface appearance of proteins involved in immune regulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / analysis
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Antigens, Differentiation, T-Lymphocyte / analysis
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CD4-Positive T-Lymphocytes / chemistry
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CD4-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / chemistry
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CD8-Positive T-Lymphocytes / metabolism*
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Cathepsin D / analysis
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Cell Degranulation*
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Cell Fractionation
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Cell Line
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Fas Ligand Protein
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Gene Expression
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Granzymes
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HeLa Cells
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Humans
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Killer Cells, Natural / chemistry
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Killer Cells, Natural / metabolism*
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Lectins, C-Type
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Lysosomes / metabolism
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Membrane Glycoproteins / analysis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Perforin
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Platelet Membrane Glycoproteins / analysis
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Pore Forming Cytotoxic Proteins
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Rats
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Serine Endopeptidases / analysis
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Tetraspanin 30
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD63 protein, human
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CD69 antigen
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Cd63 protein, mouse
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Cd63 protein, rat
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Faslg protein, rat
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Lectins, C-Type
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Membrane Glycoproteins
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Platelet Membrane Glycoproteins
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Pore Forming Cytotoxic Proteins
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Tetraspanin 30
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Perforin
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Granzymes
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Serine Endopeptidases
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GZMA protein, human
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Cathepsin D