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J. Biol. Chem., Vol. 279, Issue 43, 44931-44937, October 22, 2004

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Degradation of the Apical Sodium-dependent Bile Acid Transporter by the Ubiquitin-Proteasome Pathway in Cholangiocytes^*

Xuefeng Xia, Marlon Roundtree, Afkhamossadat Merikhi, Xiaohui Lu, Shujun Shentu, and Gene LeSage

From the Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Texas at Houston Medical School, Houston, Texas 70030

To attenuate injury during cholestasis, adaptive changes in bile acid transporter expression in the liver provide alternative bile acid excretory pathways. Apical sodium-dependent bile acid transporter (ASBT) (SLC10A2), only expressed in the liver on the cholangiocyte apical membrane, is rapidly regulated in response to inflammation and bile acids. Here, we studied the mechanisms controlling ASBT protein levels in cholangiocytes to determine whether ASBT expression is regulated by ubiquitination and disposal through the proteasome. Protein turnover assays demonstrated that ASBT is an unstable and short-lived protein. Treatment with MG-132, a proteasome inhibitor, causes time-dependent increased ASBT levels and increased intracellular accumulation of ASBT. In cells cotransfected with green fluorescent protein-tagged ASBT and hemagglutinin-tagged ubiquitin, we demonstrated coimmunoprecipitation and colocalization of ASBT and ubiquitin. Interleukin-1 (IL-1) induced down-regulation of ASBT is abrogated by a JNK inhibitor and is accompanied by an increase in ASBT polyubiquitin conjugates and a reduced ASBT half-life. In phosphorylation-deficient S335A and T339A mutants, the ASBT half-life is markedly prolonged, IL-1-induced ASBT ubiquitination is significantly reduced, and IL-1 fails to increase ASBT turnover. These results indicate that ASBT undergoes ubiquitin-proteasome degradation under basal conditions and that ASBT proteasome disposal is increased by IL-1 due to JNK-regulated serine/threonine phosphorylation of ASBT protein at both Ser-335 and Thr-339. These studies are the first report of regulation of a bile acid transporter expression by the ubiquitin-proteasome pathway.

Received for publication, January 28, 2004 , and in revised form, August 9, 2004.

^* This work was supported by Grant NIDDK RO1 DK 54208 from the NIDDK National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, University of Texas at Houston Medical School, 6431 Fannin, MSB 4.234, Houston, TX 770030. Tel.: 713-500-6677; Fax: 713-500-6699; E-mail: Gene.LeSage{at}uth.tmc.edu.

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