Abstract
Caspase-8, a proapoptotic protease, has an essential role in lymphocyte activation and protective immunity. We show that caspase-8 deficiency (CED) in humans and mice specifically abolishes activation of the transcription factor nuclear factor kappaB (NF-kappaB) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells. Caspase-8 also causes the alphabeta complex of the inhibitor of NF-kappaB kinase (IKK) to associate with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex. Recruitment of the IKKalpha, beta complex, its activation, and the nuclear translocation of NF-kappaB require enzyme activity of full-length caspase-8. These findings thus explain the paradoxical association of defective apoptosis and combined immunodeficiency in human CED.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Apoptosis
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Caspase 8
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Caspases / genetics
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Caspases / metabolism*
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Cell Line
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Cell Nucleus / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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Humans
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I-kappa B Kinase
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Immunity, Innate
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Immunologic Deficiency Syndromes / immunology
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Immunologic Deficiency Syndromes / metabolism
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Isoenzymes / metabolism
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lipopolysaccharides / immunology
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Lymphocyte Activation
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Membrane Glycoproteins / metabolism
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Mice
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Mutation
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NF-kappa B / metabolism*
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Phosphorylation
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Protein Kinase C / metabolism
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Protein Kinase C-theta
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Antigen, T-Cell / immunology*
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Receptors, Cell Surface / metabolism
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Receptors, IgG / immunology
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Signal Transduction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factor RelA
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Transfection
Substances
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Amino Acid Chloromethyl Ketones
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Cysteine Proteinase Inhibitors
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Isoenzymes
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Antigen, T-Cell
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Receptors, Cell Surface
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Receptors, IgG
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TLR4 protein, human
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factor RelA
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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PRKCQ protein, human
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Protein Kinase C
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Protein Kinase C-theta
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8
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Caspases