title: Regulation of ubiquitin-proteasome system-mediated Tip110 protein degradation by USP15.
abstract: Tip110 is a nuclear protein and has been shown to function in tumor antigenicity, regulation of gene transcription, pre-mRNA splicing, stem cell proliferation and differentiation, and embryonic development. To characterize the in vivo functions of Tip110, a transgene cassette expressing human Tip110 protein (hTip110) was used to generate hTip110 transgenic (Tg) mice. Unexpectedly, only Tip110 mRNA but not Tip110 protein was expressed in Tg MEF and tissues. Treatment of Tg MEF with proteasome inhibitors led to detection of hTip110 protein, which prompted us to investigate the regulatory mechanisms of Tip110 degradation in mouse cells. We found that hTip110 was more sensitive to ubiquitin-proteasome system (UPS)-mediated protein degradation than mouse Tip110 (mTip110), likely resulting from more hTip110 ubiquitination. Using affinity chromatography and proteomics, we identified USP15, a deubiquitinating enzyme, to be associated with Tip110. Tip110 expression led to re-distribution of USP15 from the cytoplasm to the nucleus and complete co-localization of Tip110 with USP15 in the nucleus, whereas USP15 expression resulted in hTip110 deubiquitination. Interestingly, USP15 knockdown restored hTip110 protein expression in Tg MEF and USP15 expression had little effects. Taken together, these results provide insights into the regulatory mechanism of human Tip110 degradation by USP15.
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA. Electronic address: khalid.timani@unthsc.edu.
authors.forename: Khalid Amine
authors.initials: KA
authors.lastname: Timani
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Attaya
authors.initials: A
authors.lastname: Suvannasankha
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: He
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D015153:Blotting, Western; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C416530:SART3 protein, human; D014452:Ubiquitins; D064570:Ubiquitin-Specific Proteases; C579225:Usp15 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Protein degradation; Tip110/SART3; USP15; Ubiquitin proteasome system