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PMID:14695475
| Citation |
Zhou, H, Wertz, I, O'Rourke, K, Ultsch, M, Seshagiri, S, Eby, M, Xiao, W and Dixit, VM (2004) Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 427:167-71 |
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| Abstract |
The NF-kappaB family of transcription factors is activated in response to many stimuli, including pro-inflammatory cytokines, environmental stresses and, in the case of B and T lymphocytes, by antigenic stimulation. Bcl10 is essential for NF-kappaB activation by T- and B-cell receptors. T and B lymphocytes from Bcl10-deficient mice fail to activate NF-kappaB in response to antigen-receptor stimulation and, as a consequence, are unable to proliferate. Bcl10 overexpression is sufficient to activate NF-kappaB, a process that requires the NF-kappaB essential modulator NEMO (also known as IKK-gamma), which is the regulatory subunit of the IkappaB kinase complex. However, the cellular mechanism by which Bcl10 activates the NF-kappaB pathway remains unclear. Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-kappaB activation. Paracaspase and a ubiquitin-conjugating enzyme (UBC13) were both required for Bcl10-induced NEMO ubiquitination and subsequent NF-kappaB activation. Furthermore, short interfering RNAs that reduced the expression of paracaspase and UBC13 abrogated the effects of Bcl10. Thus, the adaptor protein Bcl10 promotes activation of NF-kappaB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO. |
| Links |
PubMed Online version:10.1038/nature02273 |
| Keywords |
Adaptor Proteins, Signal Transducing; Caspases; Cell Line; Gene Deletion; Humans; I-kappa B Kinase; Jurkat Cells; Lymphoma, B-Cell, Marginal Zone/metabolism; NF-kappa B/metabolism; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Signal Transduction; Substrate Specificity; Ubiquitin/metabolism; Ubiquitin-Conjugating Enzymes/metabolism |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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