1. Academic Validation
  2. Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells

Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells

  • Nat Cell Biol. 2011 Feb;13(2):142-52. doi: 10.1038/ncb2153.
Zhi Huang 1 Qiulian Wu Olga A Guryanova Lin Cheng Weinian Shou Jeremy N Rich Shideng Bao
Affiliations

Affiliation

  • 1 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
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.

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