title: GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation.
abstract: Clearance of circulating low-density lipoprotein cholesterol (LDLc) by hepatic LDL receptors (LDLR) is central for vascular health. Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels. Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR. Herein, we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein. Depletion of GRP94 did not affect calcium homeostasis, induce ER stress, nor did it alter PCSK9 processing or its secretion but greatly increased its capacity to induce LDLR degradation. Accordingly, we found that hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels correlated with ∼ 80% reduction in hepatic LDLR protein levels. Thus, we provide evidence that, in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER.
authors.affiliation: Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Poirier
authors.affiliation: Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, QC H1T 1C8, Canada.
authors.forename: Maya
authors.initials: M
authors.lastname: Mamarbachi
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089-9176, USA.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089-9176, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada. Electronic address: gaetan.mayer@icm-mhi.org.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Mayer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood*; D002850:Chromatography, Gel; D022781:Hepatocytes / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D014162:Transfection
chemical_list: D008562:Membrane Glycoproteins; D011973:Receptors, LDL; C053387:endoplasmin; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases