title: Cezanne (OTUD7B) regulates HIF-1α homeostasis in a proteasome-independent manner.
abstract: The transcription factor HIF-1α is essential for cells to rapidly adapt to low oxygen levels (hypoxia). HIF-1α is frequently deregulated in cancer and correlates with poor patient prognosis. Here, we demonstrate that the deubiquitinase Cezanne regulates HIF-1α homeostasis. Loss of Cezanne decreases HIF-1α target gene expression due to a reduction in HIF-1α protein levels. Surprisingly, although the Cezanne-regulated degradation of HIF-1α depends on the tumour suppressor pVHL, hydroxylase and proteasome activity are dispensable. Our data suggest that Cezanne is essential for HIF-1α protein stability and that loss of Cezanne stimulates HIF-1α degradation via proteasome-independent routes, possibly through chaperone-mediated autophagy.
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Institute of Biochemistry II, Goethe University, Frankfurt (Main), Germany Medical Research Council Laboratory of Molecular Biology, Cambridge, UK bremm@em.uni-frankfurt.de s.rocha@dundee.ac.uk dk@mrc-lmb.cam.ac.uk.
authors.forename: Anja
authors.identifier: http://orcid.org/0000-0003-1386-0926
authors.initials: A
authors.lastname: Bremm
authors.affiliation: College of Life Sciences, Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Moniz
authors.affiliation: Buchmann Institute for Molecular Life Sciences, Institute of Biochemistry II, Goethe University, Frankfurt (Main), Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mader
authors.affiliation: College of Life Sciences, Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK bremm@em.uni-frankfurt.de s.rocha@dundee.ac.uk dk@mrc-lmb.cam.ac.uk.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, UK bremm@em.uni-frankfurt.de s.rocha@dundee.ac.uk dk@mrc-lmb.cam.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Komander
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010450:Endopeptidases; C476458:OTUD7B protein, human; D046988:Proteasome Endopeptidase Complex
keywords: Cezanne; HIF‐1α; Lys11‐linked ubiquitin chains; hypoxia; ubiquitin