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Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity.

Ubiquitination regulates the stability and/or activity of numerous cellular proteins. The corollary is that de-ubiquitinating enzymes, which 'trim' polyubiquitin chains from specific substrate proteins, play key roles in controlling fundamental cellular activities. Ubiquitin is essential at several stages during the activation of NF-kappaB (nuclear factor kappaB), a central co-ordinator of inflammation and other immune processes. Ubiquitination is known to cause degradation of the inhibitory molecule IkappaBalpha (inhibitor of kappaB). In addition, activation of TRAF (tumour-necrosis-factor-receptor-associated factor) and IKKgamma (IkappaB kinase gamma)/NEMO (NF-kappaB essential modifier) signal adaptors relies on their modification with 'nonclassical' forms of polyubiquitin chains. Ubiquitin also plays a key role in determining cell fate by modulating the stability of numerous pro-apoptotic or anti-apoptotic proteins. The zinc-finger protein A20 has dual functions in inhibiting NF-kappaB activation and suppressing apoptosis. The molecular mechanisms of these anti-inflammatory and cytoprotective effects are unknown. Here we demonstrate that A20 is a de-ubiquitinating enzyme. It contains an N-terminal catalytic domain that belongs to the ovarian-tumour superfamily of cysteine proteases. A20 cleaved ubiquitin monomers from branched polyubiquitin chains linked through Lys48 or Lys63 and bound covalently to a thiol-group-reactive, ubiquitin-derived probe. Mutation of a conserved cysteine residue in the catalytic site (Cys103) abolished these activities. A20 did not have a global effect on ubiquitinated cellular proteins, which indicates that its activity is target-specific. The biological significance of the catalytic domain is unknown.

Pubmed ID: 14748687

Authors

  • Evans PC
  • Ovaa H
  • Hamon M
  • Kilshaw PJ
  • Hamm S
  • Bauer S
  • Ploegh HL
  • Smith TS

Journal

The Biochemical journal

Publication Data

March 15, 2004

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 1R01 GM62502

Mesh Terms

  • Animals
  • Catalytic Domain
  • Cell Line
  • Cell Survival
  • DNA-Binding Proteins
  • Endopeptidases
  • Humans
  • Hydrolysis
  • Inflammation
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Polyubiquitin
  • Proteins
  • Ubiquitins
  • Zinc Fingers