Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity
Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity
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DOI：
10.1042/bj20031377
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发表时间：
2004-03-15
影响因子：
4.1
通讯作者：
Smith, TS
中科院分区：
文献类型：
--
作者：
Evans, PC;Ovaa, H;Smith, TS
泛素化调节许多细胞蛋白质的稳定性和/或活性。其必然结果是，去泛素化酶，从特定的底物蛋白质“修剪”聚泛素链，在控制基本的细胞活动中发挥关键作用。泛素在NF-κ B（核因子κ B）活化过程中的几个阶段是必不可少的，NF-κ B是炎症和其他免疫过程的中心协调者。已知泛素化引起抑制性分子IkappaBa（kappaB抑制剂）的降解。此外，TRAF（肿瘤坏死因子受体相关因子）和IKK γ（IkappaB激酶γ）/NEMO（NF-κ B必需修饰剂）信号衔接子的活化依赖于它们被“非经典”形式的多聚泛素链修饰。遍在蛋白还通过调节许多促凋亡或抗凋亡蛋白的稳定性在决定细胞命运方面发挥关键作用。锌指蛋白A20具有抑制NF-κ B活化和抑制细胞凋亡的双重功能。这些抗炎和细胞保护作用的分子机制尚不清楚。在这里，我们证明了A20是一种去泛素化酶。它含有一个N-末端催化结构域，属于卵巢肿瘤半胱氨酸蛋白酶超家族。A20从通过Lys（48）或Lys（63）连接的分支多聚泛素链切割泛素单体，并共价结合至巯基反应性的泛素衍生探针。在催化位点（Cys（103））中保守的半胱氨酸残基的突变消除了这些活性。A20对泛素化的细胞蛋白没有全局影响，这表明其活性是靶特异性的。催化结构域的生物学意义尚不清楚。
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 IkappaBa (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 'non-classical' 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 Lys(48) or Lys(63) and bound covalently to a thiol-group-reactive, ubiquitin-derived probe. Mutation of a conserved cysteine residue in the catalytic site (Cys(103)) 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.