title: Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other.
abstract: Amyloid precursor-like protein 2 (APLP2) and sortilin were reported to individually bind the proprotein convertase subtilisin/kexin type 9 (PCSK9) and regulate its activity on the low-density lipoprotein receptor (LDLR). The data presented herein demonstrate that mRNA knockdowns of APLP2, sortilin, or both in the human hepatocyte cell lines HepG2 and Huh7 do not affect the ability of extracellular PCSK9 to enhance the degradation of the LDLR. Furthermore, mice deficient in APLP2 or sortilin do not exhibit significant changes in liver LDLR or plasma total cholesterol levels. Moreover, cellular overexpression of one or both proteins does not alter PCSK9 secretion, or its activity on the LDLR. We conclude that PCSK9 enhances the degradation of the LDLR independently of either APLP2 or sortilin both ex vivo and in mice. Interestingly, when co-expressed with PCSK9, both APLP2 and sortilin were targeted for lysosomal degradation. Using chemiluminescence proximity and co-immunoprecipitation assays, as well as biosynthetic analysis, we discovered that sortilin binds and stabilizes APLP2, and hence could regulate its intracellular functions on other targets.
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Chutikarn
authors.initials: C
authors.lastname: Butkinaree
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Maryssa
authors.initials: M
authors.lastname: Canuel
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Rachid
authors.initials: R
authors.lastname: Essalmani
authors.affiliation: the Laboratory of Molecular Cell Biology, Montreal Heart Institute, 5000 Bélanger, Montréal, Quebec H1T 1C8, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Poirier
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Benjannet
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Asselin
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Roubtsova
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Hamelin
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Marcinkiewicz
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Ann
authors.initials: A
authors.lastname: Chamberland
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Johann
authors.initials: J
authors.lastname: Guillemot
authors.affiliation: the Laboratory of Molecular Cell Biology, Montreal Heart Institute, 5000 Bélanger, Montréal, Quebec H1T 1C8, Canada.
authors.forename: Gaétan
authors.initials: G
authors.lastname: Mayer
authors.affiliation: the Department of Neurobiology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
authors.affiliation: the Département de Virologie, Institut Pasteur, Unité de Génétique Moléculaire des Virus à ARN, F-75015 Paris, France, the CNRS, URA3015, F-75015 Paris, France, and the Université Paris Diderot, Sorbonne Paris Cité, Unité de Génétique Moléculaire des Virus à ARN, F-75015 Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Jacob
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.affiliation: From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada, seidahn@ircm.qc.ca.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL; D012697:Serine Endopeptidases; D000099183:Sortilin; C084104:APLP2 protein, human; C573412:LDLR protein, human; C472125:PCSK9 protein, human
keywords: APLP2; Sortilin (SORT1); cardiovascular disease; dyslipidemia; lipoprotein metabolism; low-density lipoprotein (LDL); low-density lipoprotein receptor (LDLR) degradation; proprotein convertase subtilisin/kexin type 9 (PCSK9)