title: A specific E3 ligase/deubiquitinase pair modulates TBP protein levels during muscle differentiation.
abstract: TFIID-a complex of TATA-binding protein (TBP) and TBP-associated factors (TAFs)-is a central component of the Pol II promoter recognition apparatus. Recent studies have revealed significant downregulation of TFIID subunits in terminally differentiated myocytes, hepatocytes and adipocytes. Here, we report that TBP protein levels are tightly regulated by the ubiquitin-proteasome system. Using an in vitro ubiquitination assay coupled with biochemical fractionation, we identified Huwe1 as an E3 ligase targeting TBP for K48-linked ubiquitination and proteasome-mediated degradation. Upregulation of Huwe1 expression during myogenesis induces TBP degradation and myotube differentiation. We found that Huwe1 activity on TBP is antagonized by the deubiquitinase USP10, which protects TBP from degradation. Thus, modulating the levels of both Huwe1 and USP10 appears to fine-tune the requisite degradation of TBP during myogenesis. Together, our study unmasks a previously unknown interplay between an E3 ligase and a deubiquitinating enzyme regulating TBP levels during cellular differentiation.
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Li
authors.identifier: http://orcid.org/0000-0002-2981-6615
authors.initials: L
authors.lastname: Li
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Silvia Sanchez
authors.initials: SS
authors.lastname: Martinez
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Hu
authors.affiliation: Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Tjian
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D008969:Molecular Sequence Data; D009132:Muscles / Q000166:cytology*; D017422:Sequence Analysis, DNA; D035181:TATA-Box Binding Protein / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D035181:TATA-Box Binding Protein; D025521:Tumor Suppressor Proteins; C579090:USP10 protein, mouse; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D043222:Ubiquitin Thiolesterase
keywords: Huwe1; TBP; USP10; biochemistry; developmental biology; differentitation; human; mouse; stem cells; ubiquitination