A research team led by Professor Wang Yan at Wuhan University (WHU) recently published a study in Circulation, revealing that PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of low-density lipoprotein receptors (LDLR) by blocking their recycling, thereby influencing blood lipid levels. The study also sheds light on the molecular basis of PCSK9 drug resistance.  

Schematic diagram of PCSK9-mediated LDLR degradation.

LDLR plays a vital role in clearing LDL cholesterol; its recycling process is essential for maintaining cholesterol balance. The study found that in an acidic environment, LDLR undergoes a conformational change that allows SNX17 to mediate its recycling back to the cell surface. However, PCSK9 binds to LDLR and prevents this conformational shift, causing LDLR to become trapped in endosomes and ultimately degraded in lysosomes. Specific LDLR mutations affecting its conformation have been identified in patients resistant to PCSK9 inhibitors.  

This research uncovers a novel mechanism by which PCSK9 regulates cholesterol metabolism and provides valuable insights for the precise application of PCSK9 inhibitors. Furthermore, it expands the understanding of regulatory mechanisms governing the degradation of type I membrane proteins.

Link to paper: https://doi.org/10.1161/CIRCULATIONAHA.124.072336