The Journal of Experimental Medicine
StemCell Technologies
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Published 1 November 2004. doi:10.1084/jem.20032246
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 9, 1167-1177
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The Molecular Adapter Carma1 Controls Entry of I{kappa}B Kinase into the Central Immune Synapse

Hiromitsu Hara2,3, Christopher Bakal2, Teiji Wada1, Denis Bouchard2, Robert Rottapel2, Takashi Saito3, and Josef M. Penninger1,2

1 IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria
2 Ontario Cancer Institute, University Health Network, and Department of Medical Biophysics and Department of Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada
3 Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan

Address correspondence to Josef M. Penninger, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohr Gasse 3-5, A-1030 Vienna, Austria. Phone: 43-1-79730-454; Fax: 43-1-79730-459; email: Josef.penninger{at}imba.oeaw.ac.at

Carma1 (also known as caspase recruitment domain [CARD]11, Bimp3) is a CARD-containing membrane-associated guanylate kinase family protein that plays an essential role in antigen receptor–induced nuclear factor {kappa}B activation. We investigated the role of Carma1 in the assembly of signaling molecules at the immune synapse using a peptide-specific system. We report that Carma1 is essential for peptide-induced interleukin 2 and interferon {gamma} production, but dispensable for proliferation in T cells. Recruitment and distribution of T cell receptor, lymphocyte function associated 1, lipid rafts, and protein kinase C (PKC){theta} to central and peripheral immune synapse regions occur normally in Carma1–/– T cells. Carma1 controls entry of I{kappa}B kinase (IKK) into lipid raft aggregates and the central region of the immune synapse, as well as activation of IKK downstream of PKC. Our data provide the first genetic evidence on a new class of molecular scaffold that controls entry of defined signaling components, IKK, into the central supramolecular activation cluster at T cell–antigen-presenting cell interfaces without having any apparent effect on the overall organization and formation of immune synapses.

Key Words: Carma1/CARD11/Bimp3 • MAGUK • T cell • IKK • immune synapse

Abbreviations used in this paper: CARD, caspase recruitment domain; cSMAC, central supramolecular activation cluster; CTx, cholera toxin; DIM, detergent insoluble material; IKK, I{kappa}B kinase; MAGUK, membrane-associated guanylate kinase; PKC, protein kinase C; pSMAC, peripheral supramolecular activation cluster; SMAC, supramolecular activation cluster; Tg, transgenic.


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