Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies.
Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies.
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DOI：
10.1091/mbc.e10-05-0449
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发表时间：
2010-12
影响因子：
3.3
通讯作者：
Hay RT
中科院分区：
文献类型：
--
作者：
Geoffroy MC;Jaffray EG;Walker KJ;Hay RT
在这里，我们分析了PML及其依赖相扑的泛素连接酶RNF4对砷的核转运动力学。我们发现，砷通过核体相关PML的相扑修饰和泛素E3连接酶RNF4的摄取，导致泛素介导的PML降解，从而诱导细胞核的快速重组。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α(RAR)融合。砷是治疗这种疾病的有效方法，因为它诱导依赖相扑的泛素介导的PML-RAR融合蛋白的蛋白酶体降解。在这里，我们分析了PML及其相扑依赖的泛素E3连接酶RNF4对砷的核转运动力学。服用砷后，PML立即转化为核体，在那里进行相扑修饰。PML最初进入核体并不依赖于RNF4，但RNF4迅速跟随PML进入核体，在那里它负责相扑修饰的PML的泛素化和蛋白酶体对其的降解。虽然砷限制了PML的流动性，但FRAP分析表明，RNF4继续以相扑依赖的方式快速穿梭到PML核体中。在这种情况下，FRET研究表明，RNF4在PML小体中与相扑相互作用，但不直接与PML相互作用。这些研究表明，砷通过核体相关PML的相扑修饰和泛素E3连接酶RNF4的摄取导致泛素介导的PML降解，从而诱导细胞核的快速重组。
Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin ligase, RNF4, in response to arsenic. We show that arsenic induces rapid reorganization of the cell nucleus by SUMO modification of nuclear body associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML. In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body-associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML.