Ubiquitin ligases HUWE1 and NEDD4 cooperatively control signal-dependent PRC2-Ezh1α/β-mediated adaptive stress response pathway in skeletal muscle cells

BackgroundWhile the role of Polycomb group protein-mediated cell memory is well established in developmental contexts, little is known about their role in adult tissues and in particular in post-mitotic cells. Emerging evidence assigns a pivotal role in cell plasticity and adaptation. PRC2-Ezh1 alpha/beta signaling pathway from cytoplasm to chromatin protects skeletal muscle cells from oxidative stress. However, detailed mechanisms controlling degradation of cytoplasmic Ezh1 beta and assembly of canonical PRC2-Ezh1 alpha repressive complex remain to be clarified.ResultsHere, we report NEDD4 ubiquitin E3 ligase, as key regulator of Ezh1 beta. In addition, we report that ubiquitination and degradation of Ezh1 beta is controlled by another layer of regulation, that is, one specific phosphorylation of serine 560 located at Ezh1 beta -specific C terminal. Finally, we demonstrate that also Ezh1 alpha needs to be stabilized under stress condition and this stabilization process requires decreased association pattern between another E3 ubiquitin ligase HUWE1.ConclusionsTogether, these results shed light on key components that regulate PRC2-Ezh1 alpha/beta pathway to direct modulation of epigenome plasticity and transcriptional output in skeletal muscle cells.