benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Immunologic-Deficiency-Syndromes

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.

Topics: Amino Acid Chloromethyl Ketones; Animals; Apoptosis; B-Lymphocytes; Caspase 8; Caspases; Cell Line; Cell Nucleus; Cysteine Proteinase Inhibitors; Humans; I-kappa B Kinase; Immunity, Innate; Immunologic Deficiency Syndromes; Isoenzymes; Killer Cells, Natural; Lipopolysaccharides; Lymphocyte Activation; Membrane Glycoproteins; Mice; Mutation; NF-kappa B; Phosphorylation; Protein Kinase C; Protein Kinase C-theta; Protein Serine-Threonine Kinases; Receptors, Antigen, T-Cell; Receptors, Cell Surface; Receptors, IgG; Signal Transduction; T-Lymphocytes; Toll-Like Receptor 4; Toll-Like Receptors; Transcription Factor RelA; Transfection