Letter abstract
Nature Cell Biology 8, 398 - 406 (2006)
Published online: 19 March 2006 | doi:10.1038/ncb1384
There is a Corrigendum (April 2006) associated with this Letter.
Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-
B activation
Chuan-Jin Wu1, Dietrich B. Conze1, Tao Li1, Srinivasa M. Srinivasula1 & Jonathan D. Ashwell1
The transcription factor NF-
B is sequestered in the cytoplasm in a complex with IB1. Almost all NF-B activation pathways converge on IB kinase (IKK), which phosphorylates IB resulting in Lys 48-linked polyubiquitination of IB and its degradation. This allows migration of NF-B to the nucleus where it regulates gene expression2. IKK has two catalytic subunits, IKK
and IKK
, and a regulatory subunit, IKK
or NEMO. NEMO is essential for NF-B activation, and NEMO dysfunction in humans is the cause of incontinentia pigmenti and hypohidrotic ectodermal dysplasia and immunodeficiency (HED–ID)3. 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)--stimulated cells, the recruitment of IKK to TNF receptor (TNF-R) 1, and the activation of IKK and NF-B. RIP is also destabilized in the absence of NEMO binding and undergoes proteasomal degradation in TNF--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-B activation.
- Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Correspondence to: Jonathan D. Ashwell1 e-mail: jda@pop.nci.nih.gov
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