Requirement for Caspase-8 in NF-κB Activation by Antigen Receptor

• Published in: Science (American Association for the Advancement of Science) Vol. 307; no. 5714; pp. 1465 - 1468
• Main Authors: Su, Helen, Bidère, Nicolas, Zheng, Lixin, Cubre, Alan, Sakai, Keiko, Dale, Janet, Salmena, Leonardo, Hakem, Razqallah, Straus, Stephen, Lenardo, Michael
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 04.03.2005
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Antigen receptors; Apoptosis; Biological and medical sciences; Cell lines; Cell nucleus; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Human immunogenetics; Immunobiology; Lymphocyte transformation; Lymphocytes; Miscellaneous; Natural killer cells; Natural killer T cells; Phosphorylation; Proteases; Receptors; Regulatory factors and their cellular receptors; T cell antigen receptors; T lymphocytes; Canada; Human; Immunoprotection; Enzyme; Rodentia; Caspase; Toll like receptor; Activation; Peptidases; Vertebrata; Mammalia; Fc-Fragment; Mouse; Hydrolases; Transcription factor NFκB; Combined immune deficiency; Apoptosis; Biological receptor
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1104765

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 κB (NF-κB) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells. Caspase-8 also causes the αβ complex of the inhibitor of NF-κB kinase (IKK) to associate with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex. Recruitment of the IKKα,β complex, its activation, and the nuclear translocation of NF-κB require enzyme activity of full-length caspase-8. These findings thus explain the paradoxical association of defective apoptosis and combined immunodeficiency in human CED.