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Cited by 254

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Dissection of the Endogenous Cellular Pathways of PCSK9-induced Low Density Lipoprotein Receptor Degradation

Poirier, Steve, Mayer, Gaetan, Poupon, Viviane, McPherson, Peter S., Desjardins, Roxane, Ly, Kevin, Asselin, Marie-Claude, Day, Robert, Duclos, Franck J., Witmer, Mark, Parker, Rex, Prat, Annik, Seidah, Nabil G.·2009·Journal of Biological Chemistry
DOI 10.1074/jbc.m109.037085
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Abstract

Elevated levels of plasma low density lipoprotein (LDL)-cholesterol, leading to familial hypercholesterolemia, are enhanced by mutations in at least three major genes, the LDL receptor (LDLR), its ligand apolipoprotein B, and the proprotein convertase PCSK9. Single point mutations in PCSK9 are associated with either hyper- or hypocholesterolemia. Accordingly, PCSK9 is an attractive target for treatment of dyslipidemia. PCSK9 binds the epidermal growth factor domain A (EGF-A) of the LDLR and directs it to endosomes/lysosomes for destruction. Although the mechanism by which PCSK9 regulates LDLR degradation is not fully resolved, it seems to involve both intracellular and extracellular pathways. Here, we show that clathrin light chain small interfering RNAs that block intracellular trafficking from the trans-Golgi network to lysosomes rapidly increased LDLR levels within HepG2 cells in a PCSK9-dependent fashion without affecting the ability of exogenous PCSK9 to enhance LDLR degradation. In contrast, blocking the extracellular LDLR endocytosis/degradation pathway by a 4-, 6-, or 24-h incubation of cells with Dynasore or an EGF-AB peptide or by knockdown of endogenous autosomal recessive hypercholesterolemia did not significantly affect LDLR levels. The present data from HepG2 cells and mouse primary hepatocytes favor a model whereby depending on the dose and/or incubation period, endogenous PCSK9 enhances the degradation of the LDLR both extra- and intracellularly. Therefore, ta…

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Crossref · 10.1074/jbc.m109.037085

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  • PCSK9 can bind newly synthesised LDLR at the trans-Golgi network and target it directly to the lysosome before it reaches the plasma membrane; disruption of this intracellular transport increases cell surface LDLR.

    “In addition, PCSK9 can bind newly synthesised LDLR at the trans-Golgi network and target it directly to the lysosome before it has reached the plasma membrane (Figure 1C), with disruption of this intracellular transport between the trans-Golgi network and lysosome resulting in an increase in cell surface LDLR [40].”

    From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [40]

Citations

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Metadata

Authors
Poirier, S., Mayer, G., Poupon, V., McPherson, P. S., Desjardins, R., Ly, K., Asselin, M.-C., Day, R., Duclos, F. J., Witmer, M., Parker, R., Prat, A., & Seidah, N. G.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2009-10
Volume
284
Issue
42
Pages
28856-28864
ISSN
0021-9258
DOI
10.1074/jbc.m109.037085
Cited by
254
References
3
Language
en
Licence

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