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J. Biol. Chem., Vol. 279, Issue 5, 3525-3534, January 30, 2004
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¶
**
From the
Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands, the ¶Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer 52621, Israel, and the ||Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033
The ubiquitin system plays an important role in endoplasmic reticulum (ER)-associated degradation of proteins that are misfolded, that fail to associate with their oligomerization partners, or whose levels are metabolically regulated. E3 ubiquitin ligases are key enzymes in the ubiquitination process as they recognize the substrate and facilitate coupling of multiple ubiquitin units to the protein that is to be degraded. The Saccharomyces cerevisiae ER-resident E3 ligase Hrd1p/Der3p functions in the metabolically regulated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and additionally facilitates the degradation of a number of misfolded proteins from the ER. In this study we characterized the structure and function of the putative human orthologue of yeast Hrd1p/Der3p, designated human HRD1. We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys48-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation. Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols. Additionally we show that human HRD1 is involved in the elimination of two model ER-associated degradation substrates, TCR-
and CD3-
.
Received for publication, July 11, 2003 , and in revised form, October 17, 2003.
* This work was supported by Dutch Cancer Society Grant KWF/RUL 98-179 (to G. H.) and by National Institutes of Health Grant GM62194 (to V. C.). 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.
Both authors contributed equally to this work.
** These authors contributed equally to this work.
To whom correspondence should be addressed. Tel.: 717-531-0020; E-mail: vchau{at}psu.edu.
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