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The p97/VCP segregase is essential for arsenic-induced degradation of PML and PML-RARA
Journal of Cell Biology ( IF 7.4 ) Pub Date : 2023-02-28 , DOI: 10.1083/jcb.202201027
Ellis G Jaffray 1 , Michael H Tatham 1 , Barbara Mojsa 1 , Magda Liczmanska 1 , Alejandro Rojas-Fernandez 1 , Yili Yin 1 , Graeme Ball 1 , Ronald T Hay 1
Affiliation  

Acute Promyelocytic Leukemia is caused by expression of the oncogenic Promyelocytic Leukemia (PML)–Retinoic Acid Receptor Alpha (RARA) fusion protein. Therapy with arsenic trioxide results in degradation of PML-RARA and PML and cures the disease. Modification of PML and PML-RARA with SUMO and ubiquitin precedes ubiquitin-mediated proteolysis. To identify additional components of this pathway, we performed proteomics on PML bodies. This revealed that association of p97/VCP segregase with PML bodies is increased after arsenic treatment. Pharmacological inhibition of p97 altered the number, morphology, and size of PML bodies, accumulated SUMO and ubiquitin modified PML and blocked arsenic-induced degradation of PML-RARA and PML. p97 localized to PML bodies in response to arsenic, and siRNA-mediated depletion showed that p97 cofactors UFD1 and NPLOC4 were critical for PML degradation. Thus, the UFD1-NPLOC4-p97 segregase complex is required to extract poly-ubiquitinated, poly-SUMOylated PML from PML bodies, prior to degradation by the proteasome.

中文翻译:


p97/VCP 分离酶对于砷诱导的 PML 和 PML-RARA 降解至关重要



急性早幼粒细胞白血病是由致癌性早幼粒细胞白血病 (PML)-视黄酸受体 Alpha (RARA) 融合蛋白的表达引起的。三氧化二砷治疗导致 PML-RARA 和 PML 降解并治愈该疾病。在泛素介导的蛋白水解之前,用 SUMO 和泛素修饰 PML 和 PML-RARA。为了确定该途径的其他成分,我们对 PML 体进行了蛋白质组学研究。这表明p97/VCP分离酶与PML体的关联在砷处理后增加。 p97 的药理抑制改变了 PML 体的数量、形态和大小,积累了 SUMO 和泛素修饰的 PML,并阻止了砷诱导的 PML-RARA 和 PML 降解。 p97 响应砷而定位于 PML 体,siRNA 介导的耗竭表明 p97 辅助因子 UFD1 和 NPLOC4 对于 PML 降解至关重要。因此,在被蛋白酶体降解之前,需要 UFD1-NPLOC4-p97 分离酶复合物从 PML 体中提取多泛素化、多 SUMO 化的 PML。
更新日期:2023-02-28
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