HIF1[alpha] deubiquitination by USP8 is essential for ciliogenesis in normoxia

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 HIF1[alpha] deubiquitinating enzyme. By counteracting pVHL-mediated ubiquitination of HIF1[alpha], USP8 maintains a basal expression of HIF1[alpha] and HIF transcriptional output in normoxia, including the repression of Rabaptin5, which is essential for endosome trafficking-mediated ciliogenesis. Synopsis This study shows that, in the presence of VHL, USP8 deubiquitination of HIF1alpha is essential to maintain ciliogenesis. Importantly, this study underscores the importance of maintaining a basal pool of HIF1a in normoxia for endosome-trafficking-mediated ciliogenesis USP8 functions as a deubiquitinating enzyme for HIF1[alpha] in normoxia USP8 antagonism of HIF1[alpha] ubiquitination by pVHL sustains basal HIF1[alpha] levels and transcriptional output Normoxic stabilization of HIF1[alpha] by USP8 is essential for ciliogenesis [PUBLICATION ABSTRACT]