The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2.
The proprotein convertase PCSK9 gene is the third locus implicated in familial hypercholesterolemia, emphasizing its role in cardiovascular diseases. Loss of function mutations and gene disruption of PCSK9 resulted in a higher clearance of plasma low density lipoprotein cholesterol, likely due to a reduced degradation of the liver low density lipoprotein receptor (LDLR). In this study, we show that two of the closest family members to LDLR are also PCSK9 targets. These include the very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) implicated in neuronal development and lipid metabolism. Our results show that wild type PCSK9 and more so its natural gain of function mutant D374Y can efficiently degrade the LDLR, VLDLR, and ApoER2 either following cellular co-expression or re-internalization of secreted human PCSK9. Such PCSK9-induced degradation does not require its catalytic activity. Membrane-bound PCSK9 chimeras enhanced the intracellular targeting of PCSK9 to late endosomes/lysosomes and resulted in a much more efficient degradation of the three receptors. We also demonstrate that the activity of PCSK9 and its binding affinity on VLDLR and ApoER2 does not depend on the presence of LDLR. Finally, in situ hybridization show close localization of PCSK9 mRNA expression to that of VLDLR in mouse postnatal day 1 cerebellum. Thus, this study demonstrates a more general effect of PCSK9 on the degradation of the LDLR family that emphasizes its major role in cholesterol and lipid homeostasis as well as brain development.
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.
Steve
S
Poirier
Gaetan
G
Mayer
Suzanne
S
Benjannet
Eric
E
Bergeron
Jadwiga
J
Marcinkiewicz
Nasha
N
Nassoury
Harald
H
Mayer
Johannes
J
Nimpf
Annik
A
Prat
Nabil G
NG
Seidah
D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D016466:CHO Cells; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008078:Cholesterol, LDL / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D021381:Protein Transport / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D008078:Cholesterol, LDL; D026502:LDL-Receptor Related Proteins; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases