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De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.

NF-kappaB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-1beta. Failure to downregulate NF-kappaB transcriptional activity results in chronic inflammation and cell death, as observed in A20-deficient mice. A20 is a potent inhibitor of NF-kappaB signalling, but its mechanism of action is unknown. Here we show that A20 downregulates NF-kappaB signalling through the cooperative activity of its two ubiquitin-editing domains. The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. Here we define a novel ubiquitin ligase domain and identify two sequential mechanisms by which A20 downregulates NF-kappaB signalling. We also provide an example of a protein containing separate ubiquitin ligase and DUB domains, both of which participate in mediating a distinct regulatory effect.

Pubmed ID: 15258597

Authors

  • Wertz IE
  • O'Rourke KM
  • Zhou H
  • Eby M
  • Aravind L
  • Seshagiri S
  • Wu P
  • Wiesmann C
  • Baker R
  • Boone DL
  • Ma A
  • Koonin EV
  • Dixit VM

Journal

Nature

Publication Data

August 5, 2004

Associated Grants

None

Mesh Terms

  • Cell Line
  • DNA-Binding Proteins
  • Down-Regulation
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Protein Structure, Tertiary
  • Proteins
  • RNA, Small Interfering
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Signal Transduction
  • TNF Receptor-Associated Factor 2
  • Ubiquitin
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases