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J. Biol. Chem., Vol. 282, Issue 45, 32665-32675, November 9, 2007

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The Hsp110 Molecular Chaperone Stabilizes Apolipoprotein B from Endoplasmic Reticulum-associated Degradation (ERAD)^*

Stacy L. Hrizo¹, Viktoria Gusarova, David M. Habiel, Jennifer L. Goeckeler, Edward A. Fisher, and Jeffrey L. Brodsky²

From the Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 and the Departments of Medicine (Cardiology) and Cell Biology, New York University School of Medicine, New York, New York 10016

Apolipoprotein B (apoB) is the most abundant protein in low density lipoproteins and plays key roles in cholesterol homeostasis. The co-translational degradation of apoB is controlled by fatty acid levels in the endoplasmic reticulum (ER) and is mediated by the proteasome. To define the mechanism of apoB degradation, we employed a cell-free system in which proteasome-dependent degradation is recapitulated with yeast cytosol, and we developed an apoB yeast expression system. We discovered that a yeast Hsp110, Sse1p, associates with and stabilizes apoB, which contrasts with data indicating that select Hsp70s and Hsp90s facilitate apoB degradation. However, the Ssb Hsp70 chaperones have no effect on apoB turnover. To determine whether our results are relevant in mammalian cells, Hsp110 was overexpressed in hepatocytes, and enhanced apoB secretion was observed. This study indicates that chaperones within distinct complexes can play unique roles during ER-associated degradation (ERAD), establishes a role for Sse1/Hsp110 in ERAD, and identifies Hsp110 as a target to lower cholesterol.

Received for publication, June 26, 2007 , and in revised form, August 30, 2007.

^* This work was supported in part by National Institutes of Health Grants HL058541 (to E. A. F. and J. L. B.) and GM75061 (to J. L. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and Figs. S1–S3.

¹ Supported in part by Predoctoral Grant 0515316U from the American Heart Association.

² To whom correspondence should be addressed: Dept. of Biological Sciences, 274 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260. Tel.: 412-624-4830; Fax: 412-624-4759; E-mail: jbrodsky{at}pitt.edu.

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