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Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation.

LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-κB pathway through linear polyubiquitination of NEMO (NF-κB essential modulator, also known as IKKγ) and RIP1. However, the regulatory mechanism of LUBAC-mediated NF-κB activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-κB activation by binding linear polyubiquitin via the C-terminal seventh zinc finger (ZF7), whereas CYLD suppresses it through deubiquitinase (DUB) activity. We determined the crystal structures of A20 ZF7 in complex with linear diubiquitin at 1.70-1.98 Å resolutions. The crystal structures revealed that A20 ZF7 simultaneously recognizes the Met1-linked proximal and distal ubiquitins, and that genetic mutations associated with B cell lymphomas map to the ubiquitin-binding sites. Our functional analysis indicated that the binding of A20 ZF7 to linear polyubiquitin contributes to the recruitment of A20 into a TNF receptor (TNFR) signalling complex containing LUBAC and IκB kinase (IKK), which results in NF-κB suppression. These findings provide new insight into the regulation of immune and inflammatory responses.

Pubmed ID: 23032187


  • Tokunaga F
  • Nishimasu H
  • Ishitani R
  • Goto E
  • Noguchi T
  • Mio K
  • Kamei K
  • Ma A
  • Iwai K
  • Nureki O


The EMBO journal

Publication Data

October 3, 2012

Associated Grants


Mesh Terms

  • Crystallography, X-Ray
  • DNA-Binding Proteins
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase
  • Intracellular Signaling Peptides and Proteins
  • Lymphoma, B-Cell
  • Mutation
  • NF-kappa B
  • Nuclear Proteins
  • Polyubiquitin
  • Protein Binding
  • Protein Conformation
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Zinc Fingers