CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation.
CARMA1 is a lymphocyte-specific member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, which coordinate signaling pathways emanating from the plasma membrane. CARMA1 interacts with Bcl10 via its caspase-recruitment domain (CARD). Here we investigated the role of CARMA1 in T cell activation and found that T cell receptor (TCR) stimulation induced a physical association of CARMA1 with the TCR and Bcl10. We found that CARMA1 was constitutively associated with lipid rafts, whereas cytoplasmic Bcl10 translocated into lipid rafts upon TCR engagement. A CARMA1 mutant, defective for Bcl10 binding, had a dominant-negative (DN) effect on TCR-induced NF-kappa B activation and IL-2 production and on the c-Jun NH(2)-terminal kinase (Jnk) pathway when the TCR was coengaged with CD28. Together, our data show that CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation and CD28 costimulation-dependent Jnk activation.
Gaide
Olivier
O
Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Favier
Benoît
B
Legler
Daniel F
DF
Bonnet
David
D
Brissoni
Brian
B
Valitutti
Salvatore
S
Bron
Claude
C
Tschopp
Jürg
J
Thome
Margot
M
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D007376:Interleukin-2 / Q000096:biosynthesis; D007527:Isoenzymes / Q000502:physiology; D019169:Jurkat Cells; D021962:Membrane Microdomains / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens; D007376:Interleukin-2; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; C426242:CARD11 protein, human; D006162:Guanylate Cyclase