Ubiquitin-specific peptidase 8 regulates the trafficking and stability of the human organic anion transporter 1.
Deubiquitination
Drug transport
Organic anion transporter
Regulation
Ubiquitin-specific peptidase
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
03
01
2020
revised:
20
07
2020
accepted:
05
08
2020
pubmed:
21
8
2020
medline:
5
1
2021
entrez:
21
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32818533
pii: S0304-4165(20)30213-0
doi: 10.1016/j.bbagen.2020.129701
pmc: PMC7863590
mid: NIHMS1666615
pii:
doi:
Substances chimiques
Endosomal Sorting Complexes Required for Transport
0
Organic Anion Transport Protein 1
0
SLC22A6 protein, human
0
Endopeptidases
EC 3.4.-
USP8 protein, human
EC 3.4.19.12
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
129701Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM079123
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM127788
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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