J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on June 1, 2004

Papers In Press, published online ahead of print March 1, 2004
J. Lipid Res., doi:10.1194/jlr.M300482-JLR200
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Submitted on November 21, 2003
Revised on February 6, 2004
Accepted on February 26, 2004

Degradation of the low-density lipoprotein receptor class 2 mutants is mediated by a proteasome-dependent pathway

Yonghe Li, Wenyan Lu, Alan L. Schwartz, and Guojun Bu

Pediatrics Dept., Washington University School of Medicine, St. Louis, MO 63110

Corresponding Author: LI_YO{at}kids.wustl.edu

Familial hypercholesterolemia is a genetic disorder which results from various gene mutations primarily within the low-density lipoprotein receptor (LDLR). Approximately 50% of the LDLR mutations are defined as class 2 mutations with the mutant proteins partially or entirely retained in the endoplasmic reticulum (ER). To determine the degradation pathway of the LDLR class 2 mutants, we examined effects of inhibition of several potential pathways on the levels of the wild-type LDLR and its four representative class 2 mutants (S156L, C176Y, E207K, and C646Y) stably expressed in Chinese hamster ovary cells. We found that proteasome inhibitors MG132 and lactacystin blocked the degradation of the LDLR mutants, but not that of the wild-type LDLR. Treatment of CHO cells with these proteasome inhibitors led to a significant accumulation of the mutants at steady-state. Furthermore, cell surface levels of the LDLR mutants were significantly increased upon inhibition of the proteasome degradation pathway. In contrast to the proteasome inhibitors, inhibitors of trypsin-like proteases, chymotrypsin-like proteases, and lysosomal pathway inhibitors did not affect the levels of the LDLR mutants. Taken together, these data demonstrate that the proteasome is the principal degradation pathway for LDLR class 2 mutants.


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