Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].

Nature cell biology | Apr 11, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16547522

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.

Pubmed ID: 16547522 RIS Download

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

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: Intramural NIH HHS, Id:

BioGRID (Data, Interactions)

Addgene (Reagent, Plasmid)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.