Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells

Zhi Huang, Qiulian Wu, Olga A. Guryanova, Lin Cheng, Weinian Shou, Jeremy N. Rich, Shideng Bao

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

The repressor element 1-silencing transcription factor (REST) functions as a master regulator to maintain neural stem/progenitor cells (NPCs). REST undergoes proteasomal degradation through β-TrCP-mediated ubiquitylation during neuronal differentiation. However, reciprocal mechanisms that stabilize REST in NPCs are undefined. Here we show that the deubiquitylase HAUSP counterbalances REST ubiquitylation and prevents NPC differentiation. HAUSP expression declines concordantly with REST on neuronal differentiation and reciprocally with β-TrCP levels. HAUSP knockdown in NPCs decreases REST and induces differentiation. In contrast, HAUSP overexpression upregulates REST by overriding β-TrCP-mediated ubiquitylation. A consensus site (310-PYSS-313) in human REST is required for HAUSP-mediated REST deubiquitylation. Furthermore, REST overexpression in NPCs rescues the differentiation phenotype induced by HAUSP knockdown. These data demonstrate that HAUSP stabilizes REST through deubiquitylation and antagonizes β-TrCP in regulating REST at the post-translational level. Thus, HAUSP-mediated deubiquitylation represents a critical regulatory mechanism involved in the maintenance of NPCs.

Original languageEnglish (US)
Pages (from-to)142-152
Number of pages11
JournalNature Cell Biology
Volume13
Issue number2
DOIs
StatePublished - Feb 2011

ASJC Scopus subject areas

  • Cell Biology

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    Huang, Z., Wu, Q., Guryanova, O. A., Cheng, L., Shou, W., Rich, J. N., & Bao, S. (2011). Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells. Nature Cell Biology, 13(2), 142-152. https://doi.org/10.1038/ncb2153