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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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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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M. Chen, Y.-H. Wang, Y. Wang, L. Huang, H. Sandoval, Y.-J. Liu, and J. Wang (2006)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. Zhou, N. Silverman, M. Hong, D. S. Liao, Y. Chung, Z. J. Chen, and T. Maniatis (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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D. R. Beisner, I. L. Ch'en, R. V. Kolla, A. Hoffmann, and S. M. Hedrick (2005)
J. Immunol. 175, 3469-3473
   Abstract »    Full Text »    PDF »
Constitutive NF-{kappa}B activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice.
P. Chugh, H. Matta, S. Schamus, S. Zachariah, A. Kumar, J. A. Richardson, A. L. Smith, and P. M. Chaudhary (2005)
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   Abstract »    Full Text »    PDF »
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M. Pellegrini, S. Bath, V. S. Marsden, D. C. S. Huang, D. Metcalf, A. W. Harris, and A. Strasser (2005)
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   Abstract »    Full Text »    PDF »
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H. Chau, V. Wong, N.-J. Chen, H.-L. Huang, W.-J. Lin, C. Mirtsos, A. R. Elford, M. Bonnard, A. Wakeham, A. I. You-Ten, et al. (2005)
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   Abstract »    Full Text »    PDF »


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