Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].
The transcription factor NF-kappaB is sequestered in the cytoplasm in a complex with IkappaB. Almost all NF-kappaB activation pathways converge on IkappaB kinase (IKK), which phosphorylates IkappaB resulting in Lys 48-linked polyubiquitination of IkappaB and its degradation. This allows migration of NF-kappaB to the nucleus where it regulates gene expression. ... IKK has two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma or NEMO. NEMO is essential for NF-kappaB activation, and NEMO dysfunction in humans is the cause of incontinentia pigmenti and hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). The recruitment of IKK to occupied cytokine receptors, and its subsequent activation, are dependent on the attachment of Lys 63-linked polyubiquitin chains to signalling intermediates such as receptor-interacting protein (RIP). Here, we show that NEMO binds to Lys 63- but not Lys 48-linked polyubiquitin, and that single point mutations in NEMO that prevent binding to Lys 63-linked polyubiquitin also abrogates the binding of NEMO to RIP in tumour necrosis factor (TNF)-alpha-stimulated cells, the recruitment of IKK to TNF receptor (TNF-R) 1, and the activation of IKK and NF-kappaB. RIP is also destabilized in the absence of NEMO binding and undergoes proteasomal degradation in TNF-alpha-treated cells. These results provide a mechanism for NEMO's critical role in IKK activation, and a key to understanding the link between cytokine-receptor proximal signalling and IKK and NF-kappaB activation.
Mesh Terms:
Biosensing Techniques, Electrophoretic Mobility Shift Assay, HeLa Cells, Humans, I-kappa B Kinase, Immunoprecipitation, Lysine, NF-kappa B, Point Mutation, Protein-Serine-Threonine Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Type I, Saccharomyces cerevisiae, Signal Transduction, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Necrosis Factor-alpha, Two-Hybrid System Techniques, Ubiquitin
Biosensing Techniques, Electrophoretic Mobility Shift Assay, HeLa Cells, Humans, I-kappa B Kinase, Immunoprecipitation, Lysine, NF-kappa B, Point Mutation, Protein-Serine-Threonine Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Type I, Saccharomyces cerevisiae, Signal Transduction, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Necrosis Factor-alpha, Two-Hybrid System Techniques, Ubiquitin
Nat. Cell Biol.
Date: Apr. 01, 2006
PubMed ID: 16547522
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