Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL
In: Cell Death & Differentiation, Jg. 29 (2022-02-22), S. 1654-1668
Online
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Zugriff:
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.
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Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL
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Autor/in / Beteiligte Person: | Shao, Xuejing ; Chen, Yingqian ; Xu, Aixiao ; Xiang, Danyan ; Wang, Wei ; Du, Wenxin ; Huang, Yunpeng ; Zhang, Xingya ; Cai, Minyi ; Xia, Zhimei ; Wang, Yi ; Cao, Ji ; Zhang, Yan ; Yang, Bo ; He, Qiaojun ; Ying, Meidan |
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Zeitschrift: | Cell Death & Differentiation, Jg. 29 (2022-02-22), S. 1654-1668 |
Veröffentlichung: | Springer Science and Business Media LLC, 2022 |
Medientyp: | unknown |
ISSN: | 1476-5403 (print) ; 1350-9047 (print) |
DOI: | 10.1038/s41418-022-00955-8 |
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