Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells

作者：Huang, Zhi; Wu, Qiulian; Guryanova, Olga A.; Cheng, Lin; Shou, Weinian; Rich, Jeremy N.; Bao, Shideng^*

来源：Nature Cell Biology, 2011, 13(2): 142-U91.

DOI：10.1038/ncb2153

• RESTRICTIVE SILENCER FACTOR
• TARGET GENES
• REST/NRSF
• REPRESSOR
• PROTEIN
• DIFFERENTIATION
• TRANSCRIPTION
• PLURIPOTENCY
• EXPRESSION
• NRSF/REST

The repressor element 1-silencing transcription factor (REST) functions as a master regulator to maintain neural stem/progenitor cells (NPCs). REST under goes proteasomal degradation through beta-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 beta-TrCP levels. HAUSP knock down in NPCs decreases REST and induces differentiation In contrast, HAUSP overexpression upregulates REST by overriding beta-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 knock down. These data demonstrate that HAUSP stabilizes REST through deubiquitylation and antagonizes beta-TrCP in regulating REST at the post-translational level. Thus, HAUSP-mediated deubiquitylation represents a critical regulatory mechanism involved in the maintenance of NPCs.

• 出版日期2011-2
• 单位上海交通大学