USP8 对 HIF1α 的去泛素化作用对于常氧条件下的纤毛发生是必需的。
HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia.
机构信息
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
出版信息
EMBO Rep. 2014 Jan;15(1):77-85. doi: 10.1002/embr.201337688. Epub 2013 Dec 30.
Abstract
Loss of primary cilia is a key feature of von Hippel-Lindau tumor suppressor (VHL)-associated pathology. Although VHL-deficiency predisposes cells to precipitous cilia disassembly in response to growth factor cues, it does not affect ciliogenesis. Here, using a siRNA-based screen to find genes that are essential for ciliogenesis only in the presence of the VHL tumor suppressor gene product pVHL, we identify ubiquitin-specific protease (USP)8. The pVHL-dependency of USP8 for ciliogenesis is directly linked to its function as a HIF1α deubiquitinating enzyme. By counteracting pVHL-mediated ubiquitination of HIF1α, USP8 maintains a basal expression of HIF1α and HIF transcriptional output in normoxia, including the repression of Rabaptin5, which is essential for endosome trafficking-mediated ciliogenesis.
摘要
主要纤毛的丧失是 von Hippel-Lindau 肿瘤抑制因子（VHL）相关病变的一个关键特征。尽管 VHL 缺失使细胞在生长因子信号的作用下容易迅速发生纤毛解体，但它并不影响纤毛发生。在这里，我们使用基于 siRNA 的筛选方法，找到了仅在 VHL 肿瘤抑制基因产物 pVHL 存在的情况下对纤毛发生至关重要的基因，即泛素特异性蛋白酶（USP）8。USP8 的纤毛发生需要 pVHL，这与其作为 HIF1α去泛素化酶的功能直接相关。通过抵消 pVHL 介导的 HIF1α泛素化，USP8 在常氧条件下维持 HIF1α和 HIF 转录输出的基础表达，包括对 Rabaptin5 的抑制，这对于内体运输介导的纤毛发生是必需的。
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