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.
Mesh Terms:
Animals, Catalytic Domain, Cell Line, Cell Survival, Endopeptidases, Humans, Hydrolysis, Inflammation, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Polyubiquitin, Proteins, Ubiquitins, Zinc Fingers
Animals, Catalytic Domain, Cell Line, Cell Survival, Endopeptidases, Humans, Hydrolysis, Inflammation, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Polyubiquitin, Proteins, Ubiquitins, Zinc Fingers
Biochem. J.
Date: Mar. 15, 2004
PubMed ID: 14748687
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