Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other

J Biol Chem. 2015 Jul 24;290(30):18609-20. doi: 10.1074/jbc.M115.647180. Epub 2015 Jun 17.


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.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / biosynthesis
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Gene Expression Regulation
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Liver / metabolism
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Proprotein Convertase 9
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism*
  • Proteolysis*
  • Receptors, LDL / biosynthesis*
  • Receptors, LDL / genetics
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*


  • APLP2 protein, human
  • Adaptor Proteins, Vesicular Transport
  • Amyloid beta-Protein Precursor
  • LDLR protein, human
  • Nerve Tissue Proteins
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
  • sortilin