T cell receptor signals to NF-κB are transmitted by a cytosolic p62-Bcl10-Malt1-IKK signalosome.
Antigen-mediated stimulation of the T cell receptor (TCR) triggers activation of nuclear factor κB (NF-κB), a key transcriptional regulator of T cell proliferation and effector cell differentiation. TCR signaling to NF-κB requires both the Carma1-Bcl10-Malt1 (CBM) complex and the inhibitor of κB (IκB) kinase (IKK) complex; however, the molecular mechanisms connecting the CBM complex to activation of IKK are incompletely defined. We found that the active IKK complex is a component of a TCR-dependent cytosolic Bcl10-Malt1 signalosome containing the adaptor protein p62, which forms in effector T cells. Phosphorylated IκBα and NF-κB were transiently recruited to this signalosome before NF-κB translocated to the nucleus. Inhibiting the activity of the kinase TAK1 or IKK blocked the phosphorylation of IKK, but not the formation of p62-Bcl10-Malt1 clusters, suggesting that activation of IKK occurs after signalosome assembly. Furthermore, analysis of T cells from p62-deficient mice demonstrated that the p62-dependent clustering of signaling components stimulated activation of NF-κB in effector T cells. Thus, TCR-stimulated activation of NF-κB requires the assembly of cytosolic p62-Bcl10-Malt1-IKK signalosomes, which may ensure highly regulated activation of NF-κB in response to TCR engagement.
Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA.
Suman
S
Paul
Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA.
Maria K
MK
Traver
Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA.
Anuj K
AK
Kashyap
Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA.
Michael A
MA
Washington
Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA.
Joseph R
JR
Latoche
Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA. Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD 20814, USA. brian.schaefer@usuhs.edu.
Brian C
BC
Schaefer
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases; D006360:Heat-Shock Proteins; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D000071456:Sequestosome-1 Protein; D000099151:MAP Kinase Kinase Kinase 7; C488088:Bcl10 protein, mouse; C101343:Sqstm1 protein, mouse; C496564:Chuk protein, mouse; C498509:Malt1 protein, mouse