Deubiquitinase HAUSP Stabilizes REST and Promotes Maintenance of Neural Progenitor Cells

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 ubiquitination during neuronal differentiation. However, reciprocal mechanisms that stabilize REST in NPCs are undefined. Here we show that deubiquitinase HAUSP counterbalances REST ubiquitination and prevents NPC differentiation. HAUSP expression declines concordantly with REST upon neuronal differentiation and reciprocally with β-TrCP levels. HAUSP knockdown in NPCs decreases REST and induces differentiation. In contrast, HAUSP overexpression up-regulates REST by overriding β-TrCP-mediated ubiquitination. A consensus site (310-PYSS-313) of human REST is required for HAUSP-mediated REST deubiquitination. Furthermore, REST overexpression in NPCs rescues the differentiation phenotype induced by HAUSP knockdown. These data demonstrate that HAUSP stabilizes REST through deubiquitination and antagonizes β-TrCP in regulating REST at post-translational level. Thus, the HAUSP-mediated deubiquitination represents a critical regulatory mechanism involved in the maintenance of NPCs.