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Molecular Pharmacology

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Research ArticleArticle

Short-Chain Ubiquitination Is Associated with the Degradation Rate of a Cell-Surface-Resident Bile Salt Export Pump (BSEP/ABCB11)

Hisamitsu Hayashi and Yuichi Sugiyama
Molecular Pharmacology January 2009, 75 (1) 143-150; DOI: https://doi.org/10.1124/mol.108.049288
Hisamitsu Hayashi
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Yuichi Sugiyama
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Abstract

The reduced expression of the bile salt export pump (BSEP/ABCB11) at the canalicular membrane is associated with cholestasis-induced hepatotoxicity due to the accumulation of bile acids in hepatocytes. We demonstrated previously that 4-phenylbutyrate (4PBA) treatment, a U.S. Food and Drug Administration-approved drug for the treatment of urea cycle disorders, induces the cell-surface expression of BSEP by prolonging the degradation rate of cell-surface-resident BSEP. On the other hand, BSEP mutations, E297G and D482G, found in progressive familial intrahepatic cholestasis type 2 (PFIC2), reduced it by shortening the degradation rate of cell-surface-resident BSEP. Therefore, to help the development of the medical treatment of cholestasis, we investigated the underlying mechanism by which 4PBA and PFIC2-type mutations affect the BSEP degradation from cell surface, focusing on short-chain ubiquitination. In Madin-Darby canine kidney II (MDCK II) cells expressing BSEP and rat canalicular membrane vesicles, the molecular mass of the mature form of BSEP/Bsep shifted from 170 to 190 kDa after ubiquitin modification (molecular mass, 8 kDa). Ubiquitination susceptibility of BSEP/Bsep was reduced in vitro and in vivo by 4PBA treatment and, conversely, was enhanced by BSEP mutations E297G and D482G. Moreover, biotin-labeling studies using MDCK II cells demonstrated that the degradation of cell-surface-resident chimeric protein fusing ubiquitin to BSEP was faster than that of BSEP itself. In conclusion, BSEP/Bsep is modified with two to three ubiquitins, and its ubiquitination is modulated by 4PBA treatment and PFIC2-type mutations. Modulation of short-chain ubiquitination can regulate the change in the degradation rate of cell-surface-resident BSEP by 4PBA treatment and PFIC2-type mutations.

Footnotes

  • This work was supported by The Grant-in-Aid for Scientific Research on Priority Areas “Transportsome” (18059007).

  • ABBREVIATIONS: BSEP/Bsep, human/rat isoforms of bile salt export pump; ER, endoplasmic reticulum; Eps15, epidermal-growth factor receptor pathway substrate 15; GFP, green fluorescence protein; MDCK, Madin-Darby canine kidney; PFIC, progressive familial intrahepatic cholestasis; rCMV, rat canalicular membrane vesicle; SD, Sprague-Dawley; Ub, ubiquitin; 4PBA, 4-phenylbutyrate; HA, hemagglutinin; PCR, polymerase chain reaction; PAGE, polyacrylamide gel electrophoresis; EndoH, endoglycosidase H; PNGaseF, peptide N-glycosidase F; EGFR, epidermal growth factor receptor; CFTR, cystic fibrosis transmembrane conductance regulator; AQP2, aquaporin-2 water channel.

    • Received May 29, 2008.
    • Accepted September 30, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (1)
Molecular Pharmacology
Vol. 75, Issue 1
1 Jan 2009
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Research ArticleArticle

Short-Chain Ubiquitination Is Associated with the Degradation Rate of a Cell-Surface-Resident Bile Salt Export Pump (BSEP/ABCB11)

Hisamitsu Hayashi and Yuichi Sugiyama
Molecular Pharmacology January 1, 2009, 75 (1) 143-150; DOI: https://doi.org/10.1124/mol.108.049288

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Research ArticleArticle

Short-Chain Ubiquitination Is Associated with the Degradation Rate of a Cell-Surface-Resident Bile Salt Export Pump (BSEP/ABCB11)

Hisamitsu Hayashi and Yuichi Sugiyama
Molecular Pharmacology January 1, 2009, 75 (1) 143-150; DOI: https://doi.org/10.1124/mol.108.049288
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