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Science 4 March 2005:
Vol. 307. no. 5714, pp. 1465 - 1468
DOI: 10.1126/science.1104765
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Reports

Requirement for Caspase-8 in NF-{kappa}B Activation by Antigen Receptor

Helen Su,1* Nicolas Bidère,1* Lixin Zheng,1 Alan Cubre,1 Keiko Sakai,1 Janet Dale,2 Leonardo Salmena,3 Razqallah Hakem,3 Stephen Straus,2 Michael Lenardo1{dagger}

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

1 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3 Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: lenardo{at}nih.gov

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