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A more recent version of this article appeared on July 1, 2007

Papers In Press, published online ahead of print April 20, 2007
J. Lipid Res., doi:10.1194/jlr.M700071-JLR200
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Submitted on February 8, 2007
Revised on March 21, 2007
Accepted on April 20, 2007

Secreted proprotein convertase subtilisin/kexin-type 9 downregulates low-density lipoprotein receptor through receptor-mediated endocytosis

Yue-Wei Qian, Robert J. Schmidt, Youyan Zhang, Shaoyou Chu, Aimin Lin, He Wang, Xiliang Wang, Thomas P. Beyer, William R. Bensch, Weiming Li, Mariam E. Ehsani, Deshun Lu, Robert J. Konrad, Patrick I. Eacho, David E. Moller, Sotirios K. Karathanasis, and Guoqing Cao

Cardiovascular Research, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285

Corresponding Author: guoqing_cao{at}lilly.com

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that regulates low-density lipoprotein receptor (LDLR) protein levels. The mechanisms of this action, however, remain to be defined. We show here that recombinant human PCSK9 expressed in human embryonic kidney 293 (HEK 293) cells was readily secreted into the medium with the prosegment associated with the c-terminal domain. Secreted PCSK9 mediated cell surface LDLR degradation in a concentration and time dependent manner when added to HEK293 cells. Accordingly, cellular LDL uptake was significantly reduced as well. When infused directly into C57B6 mice, purified human PCSK9 substantially reduced hepatic LDLR protein levels and resulted in elevated plasma LDL cholesterol. When added to culture medium, fluorescently labeled PCSK9 was endocytosed and displayed endosomal-lysosomal intracellular localization in HepG2 cells, as was demonstrated by the co-localization with DiI-LDL. PCSK9 endocytosis was mediated by LDLR as either LDLR deficiency (hepatocytes from LDLR null mice) or RNAi-mediated knockdown of LDLR markedly reduced PCSK9 endocytosis. In addition, RNAi knockdown of the autosomal recessive hypercholesterolemia gene (ARH) product also significantly reduced PCSK9 endocytosis. Biochemical analysis revealed that the LDLR extracellular domain directly interacted with secreted PCSK9; thus overexpression of LDLR extracellular domain was able to attenuate the reduction of cell surface LDLR levels by secreted PCSK9. Taken together, these results reveal that secreted PCSK9 retains biological activity, is able to bind directly to the LDLR extracellular domain, and undergoes LDLR-ARH mediated endocytosis leading to accelerated intracellular degradation of the LDLR.


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