RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation
RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation
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DOI：
10.1038/ncb1716
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发表时间：
2008-05-01
影响因子：
21.3
通讯作者：
Hay, Ronald T.
中科院分区：
文献类型：
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作者：
Tatham, Michael H.;Geoffroy, Marie-Claude;Hay, Ronald T.
在急性早幼粒细胞白血病(APL)中，早幼粒细胞白血病(PML)蛋白与维甲酸受体a(RAR)融合。砷可以有效地治疗这种疾病，砷可以通过小泛素样修饰物(SUMO)诱导PML修饰和蛋白酶体降解。在这里，我们证明了含有环状结构域的泛素E3连接酶，RNF4(也称为SNURF)，针对泛素介导的多相扑修饰蛋白的降解。RNF4耗尽或蛋白酶体抑制导致混合的、多泛素化的、多相扑的链的积累。PML蛋白在RNF4缺失的细胞中积聚，并在体外被RNF4泛素化，依赖相扑。在没有RNF4的情况下，砷不能诱导PML的降解，并且相扑修饰的PML在细胞核中积累。这些结果表明，多SUMO链可以作为单SUMO基化的离散信号，在这种情况下，靶向于泛素介导的蛋白质降解的多SUMO基化底物。
In acute promyelocytic leukaemia (APL), the promyelocytic leukaemia (PML) protein is fused to the retinoic acid receptor a (RAR). This disease can be treated effectively with arsenic, which induces PML modification by small ubiquitin-like modifiers ( SUMO) and proteasomal degradation. Here we demonstrate that the RING-domain-containing ubiquitin E3 ligase, RNF4 ( also known as SNURF), targets poly-SUMO-modified proteins for degradation mediated by ubiquitin. RNF4 depletion or proteasome inhibition led to accumulation of mixed, polyubiquitinated, poly-SUMO chains. PML protein accumulated in RNF4-depleted cells and was ubiquitinated by RNF4 in a SUMO-dependent fashion in vitro. In the absence of RNF4, arsenic failed to induce degradation of PML and SUMO-modified PML accumulated in the nucleus. These results demonstrate that poly-SUMO chains can act as discrete signals from mono-SUMOylation, in this case targeting a poly-SUMOylated substrate for ubiquitin-mediated proteolysis.