Negative feedback loop in T cell activation through IkappaB kinase-induced phosphorylation and degradation of Bcl10.
Activation of the transcription factor NF-kappaB after stimulation through antigen receptors is important for lymphocyte differentiation, activation, proliferation, and protection against apoptosis. Much progress has been made in understanding the molecular events leading to NF-kappaB activation, but how this activation is eventually down-regulated is less well understood. Recent studies have indicated that Bcl10 functions downstream of lymphocyte antigen receptors to promote the activation of the IkappaB kinase complex leading to the phosphorylation and degradation of the IkappaB inhibitors of NF-kappaB. Bcl10 has also been implicated in the pathogenesis of mucosa-associated lymphoid tissue lymphoma, possibly in association with its nuclear localization. Here, we provide evidence that the IkappaB kinase complex phosphorylates Bcl10 after T cell antigen receptor stimulation and causes its proteolysis via the beta-TrCP ubiquitin ligase/proteasome pathway. These findings document a negative regulatory activity of the IKK complex and suggest that Bcl10 degradation is part of the regulatory mechanisms that precisely control the response to antigens. Mutants of Bcl10 in the IKK phosphorylation site are resistant to degradation, accumulate in the nucleus, and lead to an increase in IL-2 production after T cell antigen receptor stimulation.
Lobry
Camille
C
Unité de Signalisation Moléculaire et Activation Cellulaire, Unité de Recherche Associée 2582, Centre National de la Recherche Scientifique, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
Lopez
Tatiana
T
Israël
Alain
A
Weil
Robert
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D002460:Cell Line; D025461:Feedback, Physiological; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
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; C491731:IKBKG protein, human; D007376:Interleukin-2; D061988:Proteasome Inhibitors; D011948:Receptors, Antigen, T-Cell; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D013912:Threonine; D012694:Serine; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex; C426242:CARD11 protein, human; D006162:Guanylate Cyclase