RYBP modulates stability and function of Ring1B through targeting UBE3A

ABSTRACT 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 RingIB 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. FASEB J. 33, 683–695 (2019). www.fasebj.org