Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL
Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL
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DOI：
10.1038/s41418-022-00955-8
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发表时间：
2022-02
影响因子：
12.4
通讯作者：
Xuejing Shao;Ying-qian Chen;Aixiao Xu;Danyan Xiang;Wei Wang;Wenxin Du;Yunpeng Huang;Xingya Zhang-Xi
中科院分区：
文献类型：
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作者：
Xuejing Shao;Ying-qian Chen;Aixiao Xu;Danyan Xiang;Wei Wang;Wenxin Du;Yunpeng Huang;Xingya Zhang-Xi
急性早幼粒细胞白血病是由原癌蛋白PML/RARα驱动的，它破坏了PML核体的构筑。PML-NBS在肿瘤抑制中起着关键作用，PML/RAR-α介导的它们的破坏加速了APL的发病。然而，PML-NB的破坏机制仍然不清楚。在这里，我们揭示了在APL中Nb组装的失败是由于辐射诱导的PML/RARα的异常相分离所致。从机制上讲，PML/RARα连接在RARα部分，这种连接增强了其与DNA的结合能力，进一步阻碍了PML部分的相分离，从而破坏了PML NB的结构。相应地，PML/RARα的脱氧核糖核酸可以恢复其相分离过程，重建功能正常的NBs，并激活RARα信号，从而抑制PML/RARα诱导的白血病发生。MLN4924对去甲肾上腺素的药理抑制在体外和体内都能根除APL细胞。我们的工作阐明了PML/RARα驱动的NB破坏的相分离机制，并强调了靶向NEDING用于根除APL。
Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RARα, which destroys the architecture of PML nuclear bodies (NBs). PML NBs are critical to tumor suppression, and their disruption mediated by PML/RARα accelerates APL pathogenesis. However, the mechanisms of PML NB disruption remain elusive. Here, we reveal that the failure of NB assembly in APL results from neddylation-induced aberrant phase separation of PML/RARα. Mechanistically, PML/RARα is neddylated in the RARα moiety, and this neddylation enhances its DNA-binding ability and further impedes the phase separation of the PML moiety, consequently disrupting PML NB construction. Accordingly, deneddylation of PML/RARα restores its phase separation process to reconstruct functional NBs and activates RARα signaling, thereby suppressing PML/RARα-driven leukemogenesis. Pharmacological inhibition of neddylation by MLN4924 eradicates APL cells both in vitro and in vivo. Our work elucidates the neddylation-destroyed phase separation mechanism for PML/RARα-driven NB disruption and highlights targeting neddylation for APL eradication.