State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Nat Commun. 2018 Mar 29;9(1):1277. doi: 10.1038/s41467-018-03498-0.
ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and many acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme. Here, using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Conserved residues implicated in RING dimerization of other TRIMs also contribute to PML tetramer stability. Wild-type PML rescues the ability of some RING mutants to form NBs as well as their sumoylation. Impaired RING tetramerization abolishes PML/RARA-driven leukemogenesis in vivo and arsenic-induced differentiation ex vivo. Our studies thus identify RING tetramerization as a key step in the NB macro-molecular scaffolding. They suggest that higher order RING interactions allow efficient UBC9 recruitment and thus change the biochemical nature of TRIM-facilitated post-translational modifications.
早幼粒细胞白血病核小体 (PML NBs) 是应激调节域，直接参与急性早幼粒细胞白血病的消除。大多数 TRIM 家族成员与泛素 E2s 结合，许多在 RING 二聚化后获得连接酶活性。相比之下，PML 结合 UBC9，即 SUMO E2 酶。在这里，我们使用 X 射线晶体学和 SAXS 表征，证明 PML RING 通过高度保守的 PML 特异性序列四聚化，这是 NB 组装和 PML 类泛素化所必需的。其他 TRIMs 的 RING 二聚化中涉及的保守残基也有助于 PML 四聚体的稳定性。野生型 PML 挽救了一些 RING 突变体形成 NB 以及它们的类泛素化的能力。受损的 RING 四聚化会在体内消除 PML/RARA 驱动的白血病发生和体外诱导的分化。因此，我们的研究将 RING 四聚化鉴定为 NB 大分子支架的关键步骤。它们表明，更高阶的 RING 相互作用允许有效的 UBC9 募集，从而改变 TRIM 促进的翻译后修饰的生化性质。
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