T-cell receptor-induced NF-kappaB activation is negatively regulated by E3 ubiquitin ligase Cbl-b.
It has previously been shown that E3 ubiquitin ligase Casitas B-lineage lymphoma-b (Cbl-b) negatively regulates T-cell activation, but the molecular mechanism(s) underlying this inhibition is not completely defined. In this study, we report that the loss of Cbl-b selectively results in aberrant activation of NF-kappaB upon T-cell antigen receptor (TCR) ligation, which is mediated by phosphatidylinositol 3-kinase (PI3-K)/Akt and protein kinase C-theta (PKC-theta). TCR-induced hyperactivation of Akt in the absence of Cbl-b may potentiate the formation of caspase recruitment domain-containing membrane-associated guanylate kinase protein 1 (CARMA1)-B-cell lymphoma/leukemia 10 (Bcl10)-mucosa-associated lymphatic tissue 1(MALT1) (CBM) complex, which appears to be independent of PKC-theta. Cbl-b associates with PKC-theta upon TCR stimulation and regulates TCR-induced PKC-theta activation via Vav-1, which couples PKC-theta to PI3-K and allows it to be phosphorylated. PKC-theta then couples IkappaB kinases (IKKs) to the CBM complex, resulting in the activation of the IKK complex. Therefore, our data provide the first evidence to demonstrate that the down-regulation of TCR-induced NF-kappaB activation by Cbl-b is mediated coordinately by both Akt-dependent and PKC-theta-dependent signaling pathways in primary T cells.
Qiao
Guilin
G
Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 5100, Suite S-521, Chicago, IL 60637, USA.
Li
Zhenping
Z
Molinero
Luciana
L
Alegre
Maria-Luisa
ML
Ying
Haiyan
H
Sun
Zuoming
Z
Penninger
Josef M
JM
Zhang
Jian
J
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018106:CD28 Antigens / Q000502:physiology; D004789:Enzyme Activation; D051550:I-kappa B Kinase / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / 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; D018106:CD28 Antigens; C496467:Card11 protein, mouse; C118387:Cblb protein, mouse; D007527:Isoenzymes; D046912:Multiprotein Complexes; D016328:NF-kappa B; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta