title: PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum.
abstract: PCSK9 (proprotein convertase subtilisin/kexin type 9) binds to the LDLR (low-density lipoprotein receptor) at the cell surface and disrupts recycling of the LDLR. However, PCSK9 also interacts with the LDLR in the ER (endoplasmic reticulum). In the present study we have investigated the role of PCSK9 for the transport of the LDLR from the ER to the cell membrane. A truncated LDLR consisting of the ectodomain (ED-LDLR) was used for these studies to avoid PCSK9-mediated degradation of the LDLR. The amount of secreted ED-LDLR was used as a measure of the amount of ED-LDLR transported from the ER. From co-transfection experiments of various PCSK9 and ED-LDLR plasmids, PCSK9 increased the amount of WT (wild-type) ED-LDLR in the medium, but not of an ED-LDLR lacking the EGF (epidermal growth factor)-A repeat or of a Class 2a mutant ED-LDLR which fails to exit the ER. Mutant PCSK9s which failed to undergo autocatalytic cleavage or failed to exit the ER, failed to increase the amount of WT-ED-LDLR in the medium. These mutants also reduced the amount of WT-ED-LDLR intracellularly, which could partly be prevented by the proteasome inhibitor lactacystine. WT-ED-LDLR promoted autocatalytic cleavage of pro-PCSK9. The findings of the present study indicate that the binding of WT-ED-LDLR to pro-PCSK9 in the ER promotes autocatalytic cleavage of PCSK9, and autocatalytically cleaved PCSK9 acts as a chaperone to promote the exit of WT-ED-LDLR from the ER.
authors.affiliation: *Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo N-0464, Norway.
authors.forename: Thea Bismo
authors.initials: TB
authors.lastname: Strøm
authors.forename: Kristian
authors.initials: K
authors.lastname: Tveten
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
mesh_terms: D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D018832:Molecular Chaperones / Q000502:physiology*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000737:chemistry / Q000502:physiology*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D011498:Protein Precursors / Q000737:chemistry / Q000502:physiology; D021381:Protein Transport; D059748:Proteolysis; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000502:physiology*
chemical_list: D018832:Molecular Chaperones; D020033:Protein Isoforms; D011498:Protein Precursors; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases