Essential role for IkappaB kinase beta in remodeling Carma1-Bcl10-Malt1 complexes upon T cell activation.
T cell receptor (TCR) signaling to IkappaB kinase (IKK)/NF-kappaB is controlled by PKCtheta-dependent activation of the Carma1, Bcl10, and Malt1 (CBM) complex. Antigen-induced phosphorylation of Bcl10 has been reported, but its physiological function is unknown. Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. Thus, our data provide evidence that IKKbeta serves a dual role upstream of its classical substrates, the IkappaB proteins. While being essential for triggering initial CBM complex formation, IKKbeta-dependent phosphorylation of Bcl10 exhibits a negative regulatory role in T cell activation.
Wegener
Elmar
E
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13095 Berlin, Germany.
Oeckinghaus
Andrea
A
Papadopoulou
Nikoletta
N
Lavitas
Liron
L
Schmidt-Supprian
Marc
M
Ferch
Uta
U
Mak
Tak W
TW
Ruland
Jürgen
J
Heissmeyer
Vigo
V
Krappmann
Daniel
D
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D051528:Guanylate Kinases / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D046912:Multiprotein Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D007376:Interleukin-2; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D051528:Guanylate Kinases; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein