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