HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 27, 19365-19374, July 6, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/27/19365    most recent M610610200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Misra, R. S. Articles by Budd, R. C. Search for Related Content PubMed PubMed Citation Articles by Misra, R. S. Articles by Budd, R. C. Social Bookmarking                      What's this?

Caspase-8 and c-FLIP_L Associate in Lipid Rafts with NF-B Adaptors during T Cell Activation^*

Ravi S. Misra¹, Jennifer Q. Russell, Andreas Koenig, Jennifer A. Hinshaw-Makepeace, Renren Wen, Demin Wang, Hairong Huo^¶, Dan R. Littman^¶, Uta Ferch^||, Jurgen Ruland^||, Margot Thome^**2, and Ralph C. Budd³

From the Immunobiology Program, Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05405-0068, the Blood Research Institute, Department of Microbiology and Molecular Genetics, Blood Center of Wisconsin, Milwaukee, Wisconsin 53201-2178, the ^¶Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, the ^||Department of Medicine (Hematology/Oncology), Technical University of Munich, Munich, Germany, and the ^**Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, 1066 Epalinges, Switzerland

Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-B signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP_L rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP_L at a known caspase-8 cleavage site. The active caspase·c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-B signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-B regulators PKC, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-B activation. The current findings define a link among TCR, caspases, and the NF-B pathway that occurs in a sequestered lipid raft environment in T cells.

Received for publication, November 15, 2006 , and in revised form, April 16, 2007.

^* This work was supported in part by National Institutes of Health Grants sAI36333, AR043520, and AI 45666 (to R. C. B.) and HL073284 (to D. W.), a grant from the Howard Hughes Medical Institute (to D. R. L.), and American Cancer Society Grant RSG CCG-106204 (to D. W.). 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.

¹ Supported by National Institutes of Health Grant 5T32ES007122.

² Supported by grants from the Swiss Science Foundation and the Swiss Cancer League (Oncosuisse).

³ To whom correspondence should be addressed: Given Medical Bldg., Burlington, VT 05405-0068. Tel.: 802-656-2286; Fax: 802-656-3854; E-mail: ralph.budd{at}uvm.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. Strauss, J. A. Lindquist, N. Arhel, E. Felder, S. Karl, T. L. Haas, S. Fulda, H. Walczak, F. Kirchhoff, and K.-M. Debatin CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling J. Exp. Med., June 8, 2009; 206(6): 1379 - 1393. [Abstract] [Full Text] [PDF]

				B. Shi, T. Tran, R. Sobkoviak, and R. M. Pope Activation-induced Degradation of FLIPL Is Mediated via the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Macrophages J. Biol. Chem., May 22, 2009; 284(21): 14513 - 14523. [Abstract] [Full Text] [PDF]

				F. D. Langel, N. A. Jain, J. S. Rossman, L. M. Kingeter, A. K. Kashyap, and B. C. Schaefer Multiple Protein Domains Mediate Interaction between Bcl10 and MALT1 J. Biol. Chem., November 21, 2008; 283(47): 32419 - 32431. [Abstract] [Full Text] [PDF]

				I. L. Ch'en, D. R. Beisner, A. Degterev, C. Lynch, J. Yuan, A. Hoffmann, and S. M. Hedrick Antigen-mediated T cell expansion regulated by parallel pathways of death PNAS, November 11, 2008; 105(45): 17463 - 17468. [Abstract] [Full Text] [PDF]

				L. M. Kingeter and B. C. Schaefer Loss of Protein Kinase C{theta}, Bcl10, or Malt1 Selectively Impairs Proliferation and NF-{kappa}B Activation in the CD4+ T Cell Subset J. Immunol., November 1, 2008; 181(9): 6244 - 6254. [Abstract] [Full Text] [PDF]

				M. Sakowicz-Burkiewicz, G. Nishanth, U. Helmuth, K. Drogemuller, D. H. Busch, O. Utermohlen, M. Naumann, M. Deckert, and D. Schluter Protein Kinase C-{theta} Critically Regulates the Proliferation and Survival of Pathogen-Specific T Cells in Murine Listeriosis J. Immunol., April 15, 2008; 180(8): 5601 - 5612. [Abstract] [Full Text] [PDF]

				E. Sharif-Askari, D. Gaucher, R. Halwani, J. Ma, K. Jao, A. Abdallah, E. K. Haddad, and R.-P. Sekaly p56Lck Tyrosine Kinase Enhances the Assembly of Death-inducing Signaling Complex during Fas-mediated Apoptosis J. Biol. Chem., December 7, 2007; 282(49): 36048 - 36056. [Abstract] [Full Text] [PDF]