Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China; and.
Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
FASEB J. 2019 Jan;33(1):683-695. doi: 10.1096/fj.201800397R. Epub 2018 Jul 24.
Ring1 and yin yang 1-binding protein (RYBP) are central components of noncanonical polycomb-repressive complex 1 (nc-PRC1), which represses target gene expression and is required for normal organismal development. However, the molecular function of RYBP in this complex is obscure. In this study, we showed that RYBP inhibits the polyubiquitination-mediated proteasomal degradation of Ring1B independently of its ubiquitin (Ub)-protein isopeptide ligase (E3) ligase activity, leading to its stabilization and increased catalytic activity toward monoubiquitination of histone H2A at lysine 119. Mechanistic dissection further disclosed that RYBP directly binds to ubiquitin protein ligase E3A (UBE3A) to promote its ubiquitination and proteasomal degradation in an autoubiquitination-independent manner. The resultant reduction of UBE3A protein level alleviates its effect on ubiquitination-mediated degradation of Ring1B, therefore resulting in increased stability and enhanced transcriptional repressor activity on its target genes. Thus, our current findings lay a foundation for understanding how RYBP functions in nc-PRC1 complexes, which is involved in development, stem cell maintenance, and carcinogenesis.-Li, M., Zhang, S., Zhao, W., Hou, C., Ma, X., Li, X., Huang, B., Chen, H., Chen, D. RYBP modulates stability and function of Ring1B through targeting UBE3A.
Ring1 和 yin yang 1 结合蛋白 (RYBP) 是非典型多梳抑制复合物 1 (nc-PRC1) 的核心组成部分，它抑制靶基因的表达，是正常机体发育所必需的。然而，RYBP 在这个复合物中的分子功能尚不清楚。在这项研究中，我们表明 RYBP 独立于其泛素 (Ub)-蛋白异肽连接酶 (E3) 连接酶活性抑制 Ring1B 的多泛素化介导的蛋白酶体降解，导致其稳定，并增加其对组蛋白 H2A 赖氨酸 119 的单泛素化的催化活性。进一步的机制分析揭示了 RYBP 直接结合泛素蛋白连接酶 E3A (UBE3A)，以促进其在自主泛素化作用下的泛素化和蛋白酶体降解。UBE3A 蛋白水平的降低减轻了其对 Ring1B 泛素化介导降解的影响，从而导致其稳定性增加，并增强了其对靶基因的转录抑制活性。因此，我们目前的发现为理解 RYBP 在涉及发育、干细胞维持和癌发生的 nc-PRC1 复合物中的功能奠定了基础。-Li, M., Zhang, S., Zhao, W., Hou, C., Ma, X., Li, X., Huang, B., Chen, H., Chen, D. RYBP 通过靶向 UBE3A 调节 Ring1B 的稳定性和功能。
