title: The herpesvirus associated ubiquitin specific protease, USP7, is a negative regulator of PML proteins and PML nuclear bodies.
abstract: The PML tumor suppressor is the founding component of the multiprotein nuclear structures known as PML nuclear bodies (PML-NBs), which control several cellular functions including apoptosis and antiviral effects. The ubiquitin specific protease USP7 (also called HAUSP) is known to associate with PML-NBs and to be a tight binding partner of two herpesvirus proteins that disrupt PML NBs. Here we investigated whether USP7 itself regulates PML-NBs. Silencing of USP7 was found to increase the number of PML-NBs, to increase the levels of PML protein and to inhibit PML polyubiquitylation in nasopharyngeal carcinoma cells. This effect of USP7 was independent of p53 as PML loss was observed in p53-null cells. PML-NBs disruption was induced by USP7 overexpression independently of its catalytic activity and was induced by either of the protein interaction domains of USP7, each of which localized to PML-NBs. USP7 also disrupted NBs formed from some single PML isoforms, most notably isoforms I and IV. CK2α and RNF4, which are known regulators of PML, were dispensable for USP7-associated PML-NB disruption. The results are consistent with a novel model of PML regulation where a deubiquitylase disrupts PML-NBs through recruitment of another cellular protein(s) to PML NBs, independently of its catalytic activity.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Feroz
authors.initials: F
authors.lastname: Sarkari
authors.forename: Xueqi
authors.initials: X
authors.lastname: Wang
authors.forename: Tin
authors.initials: T
authors.lastname: Nguyen
authors.forename: Lori
authors.initials: L
authors.lastname: Frappier
mesh_terms: D002277:Carcinoma; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000502:physiology; D005786:Gene Expression Regulation; D006564:Herpesviridae; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000235:genetics; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000473:pathology / Q000821:virology; D009687:Nuclear Proteins / Q000235:genetics*; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D020033:Protein Isoforms; D014157:Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D010450:Endopeptidases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases