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PMID:15125833

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Citation

Sun, L, Deng, L, Ea, CK, Xia, ZP and Chen, ZJ (2004) The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14:289-301

Abstract

The CARD domain protein BCL10 and paracaspase MALT1 are essential for the activation of IkappaB kinase (IKK) and NF-kappaB in response to T cell receptor (TCR) stimulation. Here we present evidence that TRAF6 ubiquitin ligase and TAK1 protein kinase mediate IKK activation by BCL10 and MALT1. RNAi-mediated silencing of MALT1, TAK1, TRAF6, and TRAF2 suppressed TCR-dependent IKK activation and interleukin-2 production in T cells. Furthermore, we have reconstituted the pathway from BCL10 to IKK activation in vitro with purified proteins of MALT1, TRAF6, TAK1, and ubiquitination enzymes including Ubc13/Uev1A. We find that a small fraction of BCL10 and MALT1 proteins form high molecular weight oligomers. Strikingly, only these oligomeric forms of BCL10 and MALT1 can activate IKK in vitro. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization, and activate the ligase activity of TRAF6 to polyubiquitinate NEMO. These results reveal an oligomerization --> ubiquitination --> phosphorylation cascade that culminates in NF-kappaB activation in T lymphocytes.

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PubMed

Keywords

Adaptor Proteins, Signal Transducing; Carrier Proteins/metabolism; Caspases; HeLa Cells; Humans; I-kappa B Kinase; Immunity, Innate/physiology; Interleukin-2/metabolism; Lymphoma, B-Cell, Marginal Zone; MAP Kinase Kinase Kinases/metabolism; Macromolecular Substances; NF-kappa B/metabolism; Neoplasm Proteins; Phosphorylation; Protein Binding/physiology; Protein-Serine-Threonine Kinases/metabolism; Proteins/metabolism; RNA Interference/physiology; Signal Transduction/physiology; T-Lymphocytes/enzymology; T-Lymphocytes/immunology; TNF Receptor-Associated Factor 2; TNF Receptor-Associated Factor 6; Transcription Factors/metabolism; Ubiquitin/metabolism; Ubiquitin-Conjugating Enzymes/metabolism

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


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