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.

The U4/U6 Recycling Factor SART3 Has Histone Chaperone Activity and Associates with USP15 to Regulate H2B Deubiquitination

“…Usp15 has been implicated in the deubiquitination of a wide variety of substrates, including proteins in the TGF␤-signaling pathway and several E3 ligases (57)(58)(59)(60)(61)(62). Although Usp4 and Usp15 sequences are very similar, they most likely perform overlapping, but non-identical, functions.…”

Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication

“…USP7 was reported to deubiquitinate REST protein to counterbalance the SCF/β-TrCP-mediated ubiquitination, thereby maintaining quality and status of a stem cell (Huang et al, 2011). Another DUB, USP15 was found to stabilize only the newly synthesized REST, which is accumulated on mitotic exit (Faronato et al, 2013). …”

A flexible microfluidic system for single-cell transcriptome profiling elucidates phased transcriptional regulators of cell cycle

“…Indeed, only 9/78 were determined as phase-specific genes in previous studies 9, 24 , thus demonstrating the merit of our alternative analysis strategy. Differentially active regulators in the absence of phased gene expression changes included YY1 which is subject to regulatory phosphorylation by various cell cycle associated kinases including Aurora A 38 and PLK1 39 , FOXM1 that is regulated by SUMOylation 40 and PLK1 phosphorylation 19 , and REST which is regulated by phosphorylation and USP15 limited polyubiquitination 41 . However, certain transcription factors such as PITX1, SATB2, NR2F2, FOXO3 and MYBL1/B-MYB were regulated at the level of gene expression, likely due to coordinated upstream activity of other master regulators in the cell cycle regulatory gene network.…”