Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells.
Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells.
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DOI：
10.1038/ncb2153
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发表时间：
2011-02
影响因子：
21.3
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中科院分区：
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阻遏物元件1沉默转录因子（REST）作为维持神经干/祖细胞（NPC）的主要调节因子发挥作用。在神经元分化过程中，REST通过β-TrCP介导的泛素化进行蛋白酶体降解。然而，在NPC中稳定REST的相互机制尚未确定。在这里，我们发现去泛素化酶HAUSP平衡REST泛素化并阻止NPC分化。在神经元分化后，HAUSP表达与REST一致下降，并且与β-TrCP水平一致下降。NPC中的HAUSP敲低降低REST并诱导分化。相反，HAUSP过表达通过覆盖β-TrCP介导的泛素化上调REST。HAUSP介导的REST去泛素化需要人REST的共有位点（310-PYSS-313）。此外，REST在NPC中的过表达挽救了由HAUSP敲低诱导的分化表型。这些数据表明，HAUSP通过去泛素化稳定REST，并在翻译后水平拮抗β-TrCP调节REST。因此，HAUSP介导的去泛素化是参与NPC维持的关键调节机制。
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.