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J. Biol. Chem. 282 (10): 7416-7423

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Essential Role for Caspase-8 in Toll-like Receptors and NF{kappa}B Signaling*


Bénédicte Lemmers{ddagger}§, Leonardo Salmena{ddagger}§, Nicolas Bidère||, Helen Su||, Elzbieta Matysiak-Zablocki{ddagger}§, Kiichi Murakami{ddagger}§, Pamela S. Ohashi{ddagger}§, Andrea Jurisicova**, Michael Lenardo||, Razqallah Hakem, Supported by a salary award from the Canadian Institute of Health Research{ddagger}§1, , and Anne Hakem{ddagger}§2

{ddagger}Ontario Cancer Institute, §The Advanced Medical Discovery Institute, and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada, the ||Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and the **Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 2X1, Canada

Abstract: In addition to its pro-apoptotic function in the death receptor pathway, roles for caspase-8 in mediating T-cell proliferation, maintaining lymphocyte homeostasis, and suppressing immunodeficiency have become evident. Humans with a germline point mutation of CASPASE-8 have multiple defects in T cells, B cells, and NK cells, most notably attenuated activation and immunodeficiency. By generating mice with B-cell-specific inactivation of caspase-8 (bcasp8-/-), we show that caspase-8 is dispensable for B-cell development, but its loss in B cells results in attenuated antibody production upon in vivo viral infection. We also report an important role for caspase-8 in maintaining B-cell survival following stimulation of the Toll-like receptor (TLR)2, -3, and -4. In response to TLR4 stimulation, caspase-8 is recruited to a complex containing IKK{alpha}beta, and its loss resulted in delayed NF{kappa}B nuclear translocation and impaired NF{kappa}B transcriptional activity. Our study supports dual roles for caspase-8 in apoptotic and nonapoptotic functions and demonstrates its requirement for TLR signaling and in the regulation of NF{kappa}B function.

Received for publication July 14, 2006. Revision received November 29, 2006.

* This work was supported in part by Canadian Institute of Health Research Grant MOP 36537 and National Cancer Institute of Canada Grant TFPP 12000. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


The on-line version of this article (available at contains supplemental Figs. S1–S3.

1 To whom correspondence may be addressed: Ontario Cancer Inst., Advanced Medical Discovery Inst., 620 University Ave., Suite 706, Toronto, Ontario M5G 2C1, Canada. Tel.: 416-946-2398; Fax: 416-204-2277; E-mail: rhakem{at} 2 To whom correspondence may be addressed: Ontario Cancer Inst., Advanced Medical Discovery Inst., 620 University Ave., Suite 706, Toronto, Ontario M5G 2C1, Canada. E-mail: ahakem{at}

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