The USP19 Deubiquitinase Regulates the Stability of c-IAP1 and c-IAP2
The USP19 Deubiquitinase Regulates the Stability of c-IAP1 and c-IAP2
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DOI：
10.1074/jbc.m111.282020
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发表时间：
2011-10-14
影响因子：
4.8
通讯作者：
Yang, Xiaolu
中科院分区：
文献类型：
--
作者：
Mei, Yide;Hahn, Allison Alcivar;Yang, Xiaolu
细胞凋亡抑制因子(IAPs)是细胞凋亡和其他基本细胞过程的重要调节因子。许多IAP是环状结构域的泛素E3连接酶，控制其相互作用蛋白的稳定性。然而，IAP的稳定性如何受到监管仍不清楚。本文报道了去泛素化酶USP19与细胞内IAP1(c-IAP1)和c-IAP2的相互作用。USP19基因敲除降低了两种c-IAP的水平，而USP19的过度表达导致c-IAP水平显著升高。USP19在体外能有效地去除c-IAP上的泛素，但在体内主要通过脱泛素酶不依赖的机制稳定c-IAP。脱泛素酶活性参与了USP19自身的稳定，这是由USP19自结合促进的。在功能上，USP19的敲除以c-IAP1和2依赖的方式增强了肿瘤坏死因子α诱导的半胱氨酸天冬氨酸酶的激活和凋亡。这些结果表明，c-IAP的自身泛素连接酶活性被USP19抑制，提示脱泛素酶参与了IAP稳定性的调节。
The inhibitors of apoptosis (IAPs) are critical regulators of apoptosis and other fundamental cellular processes. Many IAPs are RING domain-containing ubiquitin E3 ligases that control the stability of their interacting proteins. However, how IAP stability is regulated remains unclear. Here we report that USP19, a deubiquitinating enzyme, interacts with cellular IAP 1 (c-IAP1) and c-IAP2. Knockdown of USP19 decreases levels of both c-IAPs, whereas overexpression of USP19 results in a marked increase in c-IAP levels. USP19 effectively removes ubiquitin from c-IAPs in vitro, but it stabilizes c-IAPs in vivo mainly through deubiquitinase-independent mechanisms. The deubiquitinase activity is involved in the stabilization of USP19 itself, which is facilitated by USP19 self-association. Functionally, knockdown of USP19 enhances TNF alpha-induced caspase activation and apoptosis in a c-IAP1 and 2-dependent manner. These results suggest that the self-ubiquitin ligase activity of c-IAPs is inhibited by USP19 and implicate deubiquitinating ;enzymes in the regulation of IAP stability.