title: The deubiquitylase USP15 stabilizes newly synthesized REST and rescues its expression at mitotic exit.
abstract: Reversible ubiquitylation of proteins contributes to their integrity, abundance and activity. The RE1-silencing transcription factor (REST) plays key physiological roles and is dysregulated in a spectrum of disease. It is rapidly turned over and is phosphorylated, polyubiquitylated and degraded en masse during neuronal differentiation and cell cycle progression. Through siRNA screening we identified the deubiquitylase USP15 as a key regulator of cellular REST. Both antagonism of REST polyubiquitylation and rescue of endogenous REST levels are dependent on the deubiquitylase activity of USP15. However, USP15 depletion does not destabilize pre-existing REST, but rather specifically impairs de novo REST synthesis. Indeed, we find that a small fraction of endogenous USP15 is associated with polysomes. In accordance with these findings, USP15 does not antagonize the degradation of phosphorylated REST at mitosis. Instead it is required for the rapid accumulation of newly synthesized REST on mitotic exit, thus playing a key role in its cell cycle oscillations. Importantly, this study reveals a novel role for a DUB in specifically promoting new protein synthesis.
authors.affiliation: Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Faronato
authors.forename: Vruti
authors.initials: V
authors.lastname: Patel
authors.forename: Sarah
authors.initials: S
authors.lastname: Darling
authors.forename: Laura
authors.initials: L
authors.lastname: Dearden
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clague
authors.forename: Sylvie
authors.initials: S
authors.lastname: Urbé
authors.forename: Judy M
authors.initials: JM
authors.lastname: Coulson
mesh_terms: D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099229:RE1-Silencing Transcription Factor
chemical_list: D010450:Endopeptidases; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
keywords: G1; NRSF; cell cycle; co-translational; deubiquitination; post-translational modification; protein degradation; ubiquitin specific peptidase 15