Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee , Dundee, UK.
J Cell Biol. 2023 Apr 3;222(4). doi: 10.1083/jcb.202201027. Epub 2023 Feb 28.
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.
急性早幼粒细胞白血病是由致癌早幼粒细胞白血病（PML）-维甲酸受体α（RARA）融合蛋白的表达引起的。三氧化二砷治疗可导致 PML-RARA 和 PML 的降解，并治愈该疾病。SUMO 和泛素对 PML 和 PML-RARA 的修饰先于泛素介导的蛋白水解。为了鉴定该途径的其他成分，我们对 PML 体进行了蛋白质组学研究。这表明砷处理后，p97/VCP 分选酶与 PML 体的关联增加。p97 的药理学抑制改变了 PML 体的数量、形态和大小，积累了 SUMO 和泛素修饰的 PML，并阻断了砷诱导的 PML-RARA 和 PML 的降解。p97 响应砷而定位到 PML 体，siRNA 介导的消耗表明 p97 辅助因子 UFD1 和 NPLOC4 对于 PML 降解至关重要。因此，UFD1-NPLOC4-p97 分选酶复合物是将多泛素化、多 SUMO 化的 PML 从 PML 体中提取出来，然后再通过蛋白酶体进行降解所必需的。
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