Deubiquitylase 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 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.
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Zhi
Z
Huang
Qiulian
Q
Wu
Olga A
OA
Guryanova
Lin
L
Cheng
Weinian
W
Shou
Jeremy N
JN
Rich
Shideng
S
Bao
D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
D012097:Repressor Proteins; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D044844:beta-Transducin Repeat-Containing Proteins; D000099229:RE1-Silencing Transcription Factor; C464569:USP7 protein, human
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