title: HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia.
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.
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Albino
authors.initials: A
authors.lastname: Troilo
authors.forename: Irina
authors.initials: I
authors.lastname: Alexander
authors.forename: Sarah
authors.initials: S
authors.lastname: Muehl
authors.forename: Daniela
authors.initials: D
authors.lastname: Jaramillo
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002923:Cilia / Q000502:physiology*; D004705:Endocytosis; D010450:Endopeptidases / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D054875:Ubiquitination; D033921:Vesicular Transport Proteins / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C097227:RABEP1 protein, human; D033921:Vesicular Transport Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; C494469:VHL protein, mouse; D010100:Oxygen