Characterization of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Trafficking Reveals a Novel Lysosomal Targeting Mechanism via Amyloid Precursor-like Protein 2 (APLP2)

• Published in: The Journal of biological chemistry Vol. 288; no. 15; pp. 10805 - 10818
• Main Authors: DeVay, Rachel M., Shelton, David L., Liang, Hong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.04.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; APLP2; APP; Cell Biology; Cholesterol; Endocytosis - physiology; Familial Hypercholesterolemia; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; LDLR; Low Density Lipoprotein (LDL); Lysosomes; Lysosomes - genetics; Lysosomes - metabolism; Mice; Models, Biological; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; PCSK9; Proprotein Convertase 9; Proprotein Convertases - genetics; Proprotein Convertases - metabolism; Protein Degradation; Protein Transport - physiology; Proteolysis; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; APP; Low Density Lipoprotein (LDL); APLP2; Lysosomes; PCSK9; Protein Degradation; LDLR; Cholesterol; Familial Hypercholesterolemia
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M113.453373

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor protein levels by diverting it to lysosomes. Monoclonal antibody therapeutics aimed to neutralize PCSK9 have been shown to successfully lower serum LDL levels; however, we previously found that such therapeutic antibodies are subject to PCSK9-mediated clearance. In this study, we discovered that PCSK9 interacts via its C-terminal domain directly and in a pH-dependent manner with amyloid precursor protein as well as its closely related family member, amyloid precursor protein-like protein 2. Furthermore, we determined that amyloid precursor protein-like protein-2, but not amyloid precursor protein, is involved in mediating postendocytic delivery of PCSK9 to lysosomes and is therefore important for PCSK9 function. Based on our data, we propose a model for a lysosomal transport complex by which a soluble protein can target another protein for degradation from the luminal side of the membrane by bridging it to a lysosomally targeted transmembrane protein. Background: PCSK9 functions to degrade the LDLR by a previously unknown lysosomal sorting mechanism. Results: Here, we discovered and characterized a novel, pH-dependent interaction between PCSK9 and the amyloid precursor-like protein 2 (APLP2). Conclusion: APLP2 plays an integral role in postendocytic PCSK9 lysosomal sorting. Significance: These findings provide key insights into the mechanism by which PCSK9 degrades LDLR and reveal a novel lysosomal transport complex.