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 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 CONCLUSIONS: PCSK9 promotes LDLR degradation by preventing SNX17-mediated LDLR recycling. Patients with sequence variations in