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Analysis of nuclear factor-κB (NF-κB) essential modulator (NEMO) binding to linear and lysine-linked ubiquitin chains and its role in the activation of NF-κB.

Nuclear factor-κB (NF-κB) essential modulator (NEMO), a component of the inhibitor of κB kinase (IKK) complex, controls NF-κB signaling by binding to ubiquitin chains. Structural studies of NEMO provided a rationale for the specific binding between the UBAN (ubiquitin binding in ABIN and NEMO) domain of NEMO and linear (Met-1-linked) di-ubiquitin chains. Full-length NEMO can also interact with Lys-11-, Lys-48-, and Lys-63-linked ubiquitin chains of varying length in cells. Here, we show that purified full-length NEMO binds preferentially to linear ubiquitin chains in competition with lysine-linked ubiquitin chains of defined length, including long Lys-63-linked deca-ubiquitins. Linear di-ubiquitins were sufficient to activate both the IKK complex in vitro and to trigger maximal NF-κB activation in cells. In TNFα-stimulated cells, NEMO chimeras engineered to bind exclusively to Lys-63-linked ubiquitin chains mediated partial NF-κB activation compared with cells expressing NEMO that binds to linear ubiquitin chains. We propose that NEMO functions as a high affinity receptor for linear ubiquitin chains and a low affinity receptor for long lysine-linked ubiquitin chains. This phenomenon could explain quantitatively distinct NF-κB activation patterns in response to numerous cell stimuli.

Pubmed ID: 22605335


  • Kensche T
  • Tokunaga F
  • Ikeda F
  • Goto E
  • Iwai K
  • Dikic I


The Journal of biological chemistry

Publication Data

July 6, 2012

Associated Grants


Mesh Terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Embryo, Mammalian
  • Fibroblasts
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Lysine
  • Mice
  • Mice, Knockout
  • Mutation
  • NF-kappa B
  • Phosphorylation
  • Protein Binding
  • Tumor Necrosis Factor-alpha
  • Ubiquitin
  • Ubiquitin-Protein Ligases