PCSK9 Promotes LDLR Degradation by Preventing SNX17-Mediated LDLR Recycling

BACKGROUND: Low-density lipoprotein (LDL) is internalized into cells mainly through LDLR (LDL receptor)–mediated endocytosis. In an acidic endosome, LDLR is released from LDL and recycles back to the cell surface, whereas LDL is left in the endosome and degraded in the lysosome. Circulating PCSK9 (proprotein convertase subtilisin/kexin 9) binds with LDLR and is internalized into the endosome, similar to LDL. In an acidic endosome, LDLR fails to disassociate from PCSK9, and both proteins are degraded in the lysosome. PCSK9 inhibitors are widely used for treating hypercholesterolemia. However, how PCSK9 diverts LDLR to the lysosome for degradation remains elusive. Some patients are resistant to PCSK9 inhibitors, for unknown reasons. METHODS: Both in vitro and in vivo approaches were used to investigate the molecular and cellular mechanisms of PCSK9-mediated LDLR degradation. LDLR containing FH sequence variations was expressed in Ldlr knockout mice and knockout HuH7 cells to evaluate their response to PCSK9 and PCSK9 inhibitors. RESULTS: Acidic pH induces a conformational change in LDLR extracellular domain and promotes its interaction with SNX17 (sorting nexin 17) through the intracellular domain. Knocking down SNX17 abolishes LDLR recycling and causes accelerated degradation in the lysosome. PCSK9 prevents the acidic pH–induced conformational change in LDLR and blocks its interaction with SNX17. Knocking down SNX17 abolishes PCSK9-mediated LDLR degradation. Any FH sequence variations that disrupt LDLR recycling are unresponsive to PCSK9 or PCSK9 inhibitors, even though they can internalize LDL. CONCLUSIONS: PCSK9 promotes LDLR degradation by preventing SNX17-mediated LDLR recycling. Patients with sequence variations in FH leading to defects in LDLR recycling are resistant to PCSK9 inhibitors. Genetic diagnosis and alternative drugs independent of LDLR will be needed for treatment of these patients.