Ubiquitin-specific peptidase 8 regulates the trafficking and stability of the human organic anion transporter 1
Autor: | Jinghui Zhang, Chenchang Liu, Guofeng You |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Organic anion transporter 1 media_common.quotation_subject Cell Biophysics Biochemistry Article 03 medical and health sciences Organic Anion Transport Protein 1 0302 clinical medicine Ubiquitin Chlorocebus aethiops Endopeptidases medicine Animals Humans Internalization Molecular Biology media_common Gene knockdown Endosomal Sorting Complexes Required for Transport biology Protein Stability Chemistry Ubiquitination Transporter Cell biology Protein Transport 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Biotinylation COS Cells biology.protein Ubiquitin Thiolesterase Deubiquitination |
Zdroj: | Biochim Biophys Acta Gen Subj |
ISSN: | 0304-4165 |
Popis: | BACKGROUND: Organic anion transporter 1 (OAT1) plays a vital role in avoiding the potential toxicity of various anionic drugs through the involvement of kidney elimination. We previously demonstrated that ubiquitin conjugation to OAT1 led to OAT1 internalization from cell surface, followed by degradation. Ubiquitination is a dynamic process, where deubiquitination is catalyzed by a class of ubiquitin-specific peptidases. METHODS: The role of ubiquitin-specific peptidase 8 (USP8) in hOAT1 function, expression and ubiquitination was assessed by conducting transporter uptake assay, biotinylation assay and ubiquitination assay. RESULTS: We demonstrated that USP8 overexpression in hOAT1-expressing cells led to an increased hOAT1 transporter activity and expression, which correlated well with a reduced hOAT1 ubiquitination. Such phenomenon was not observed in inactive USP8 mutant-transfected cells. In addition, the knockdown of endogenous USP8 by USP8-specific siRNA resulted in an increased hOAT1 ubiquitination, which correlated well with a decrease in hOAT1 expression and transport activity. Biotinylation experiments demonstrated that USP8-induced increase in hOAT1 expression and transport activity occurred through a deceleration of the rates of hOAT1 internalization and degradation. CONCLUSIONS: These results indicated the regulatory role of USP8 in OAT1 function, expression, trafficking, and stability. GENERAL SIGNIFICANCE: USP8 could be a new target for modulating OAT1-mediated drug transport. |
Databáze: | OpenAIRE |
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