Requirement for caspase-8 in NF-kappaB activation by antigen receptor.
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.
Su
Helen
H
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Bidère
Nicolas
N
Zheng
Lixin
L
Cubre
Alan
A
Sakai
Keiko
K
Dale
Janet
J
Salmena
Leonardo
L
Hakem
Razqallah
R
Straus
Stephen
S
Lenardo
Michael
M
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014162:Transfection
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases