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.
Evans
Paul C
PC
Molecular Immunology Programme, The Babraham Institute, Cambridge CB2 4AT, UK. paul.evans@bbsrc.ac.uk
Ovaa
Huib
H
Hamon
Maureen
M
Kilshaw
Peter J
PJ
Hamm
Svetlana
S
Bauer
Stefan
S
Ploegh
Hidde L
HL
Smith
Trevor S
TS
D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007249:Inflammation / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D025821:Polyubiquitin / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014452:Ubiquitins / Q000378:metabolism*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D014452:Ubiquitins; D025821:Polyubiquitin; D010450:Endopeptidases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3