Common Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Epitopes Mediate Multiple Routes for Internalization and...

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Medicine

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is crucial for regulating low-density lipoprotein cholesterol (LDL-C) levels by targeting the low-density lipoprotein receptor (LDLR) for lysosomal degradation.
• The precise molecular mechanisms underlying PCSK9-mediated receptor internalization and degradation remain incompletely elucidated.

Purpose of the Study:

• To investigate the detailed mechanism by which PCSK9 mediates the internalization of LDLR and other receptors.
• To identify potential co-receptors or interacting proteins involved in PCSK9 endocytosis.
• To elucidate the broader role of identified interaction partners in PCSK9 function.

Main Methods:

• Cell-based assays using hepatocytes to study protein-protein interactions and endocytosis.
• Investigating PCSK9 interactions with LDLR and amyloid precursor like protein 2 (APLP2) at neutral pH.
• Assessing the role of LDL and APLP2 in PCSK9 endocytosis and APOER2 degradation.

Main Results:

• Low-density lipoprotein receptor (LDLR) facilitates PCSK9 interaction with amyloid precursor like protein 2 (APLP2), leading to PCSK9 internalization independently of direct PCSK9-LDLR binding.
• Binding to either APLP2 or LDLR is sufficient for PCSK9 endocytosis in hepatocytes.
• LDL competes with APLP2 for PCSK9 binding, indirectly mediating PCSK9 endocytosis.
• APLP2 and LDLR are essential for the degradation of another PCSK9 target, APOER2.

Conclusions:

• PCSK9 utilizes at least two distinct endocytic epitopes for internalization.
• LDLR and APLP2 play a general and critical role in mediating PCSK9 function and the degradation of its targets.
• These findings provide a refined understanding of how PCSK9 directs proteins to lysosomes, impacting LDL-C metabolism.