B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis
B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis
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B1 寡聚化调节 PML 核体生物发生和白血病发生
DOI：
10.1038/s41467-019-11746-0
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发表时间：
2019-08-22
影响因子：
16.6
通讯作者：
Meng, Guoyu
中科院分区：
文献类型：
--
作者：
Li, Yuwen;Ma, Xiaodan;Meng, Guoyu
原髓细胞白血病（PML）蛋白可聚集成直径为0.1-2 μ m的百万道尔顿核组装体。PML核体生物发生的机制仍不清楚。在这里，PMLRBCC被成功纯化。凝胶过滤和超离心分析表明，以前未认识到的顺序寡聚化机制，通过PML单体，二聚体，四聚体和N-mer。一致地，PML B1盒结构（2.0埃）和SAXS表征揭示了W157-，F158-和SD 1-接口的意外联网。基于结构的扰动，在这些B1接口不仅损害寡聚体在体外，但也取消PML类小泛素化和核体的生物合成在HeLaPml-/-细胞。更重要的是，如使用转基因小鼠的体内研究所证明的，PML-RAR α（PR）F158 E排除了白血病发生。此外，单细胞RNA测序分析表明，B1寡聚化是PML-RAR α驱动的反式激活的重要调节因子。总而言之，这些结果不仅定义了以前未被认识到的PML中的B1盒寡聚化，而且还强调了寡聚化是致癌的重要因素。
ProMyelocyticLeukemia (PML) protein can polymerize into a mega-Dalton nuclear assembly of 0.1-2 mu m in diameter. The mechanism of PML nuclear body biogenesis remains elusive. Here, PMLRBCC is successfully purified. The gel filtration and ultracentrifugation analysis suggest a previously unrecognized sequential oligomerization mechanism via PML monomer, dimer, tetramer and N-mer. Consistently, PML B1-box structure (2.0 angstrom) and SAXS characterization reveal an unexpected networking by W157-, F158- and SD1-interfaces. Structure-based perturbations in these B1 interfaces not only impair oligomerization in vitro but also abolish PML sumoylation and nuclear body biogenesis in HeLaPml-/- cell. More importantly, as demonstrated by in vivo study using transgenic mice, PML-RAR alpha (PR) F158E precludes leukemogenesis. In addition, single cell RNA sequencing analysis shows that B1 oligomerization is an important regulator in PML-RAR alpha-driven transactivation. Altogether, these results not only define a previously unrecognized B1-box oligomerization in PML, but also highlight oligomerization as an important factor in carcinogenesis.