GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation

Area of Science:

• Molecular Biology
• Cellular Biology
• Cardiovascular Research

Background:

• Hepatic LDL receptors (LDLR) clear circulating low-density lipoprotein cholesterol (LDLc), vital for vascular health.
• PCSK9, secreted by hepatocytes, promotes LDLR degradation, elevating plasma LDLc.
• The mechanism preventing LDLR degradation when co-existing with PCSK9 in hepatocytes remains unclear.

Purpose of the Study:

• To identify proteins involved in regulating the interaction between PCSK9 and LDLR within the hepatocyte secretory pathway.
• To elucidate the role of GRP94 in modulating PCSK9-mediated LDLR degradation.

Main Methods:

• Identification of GRP94 as a binding protein for PCSK9 and LDLR.
• Depletion of GRP94 in hepatocytes to assess its impact on LDLR degradation.
• Analysis of hepatocyte-specific Grp94-deficient mice to evaluate in vivo effects on plasma LDLc and hepatic LDLR levels.

Main Results:

• GRP94 binds to the C-terminal domain of PCSK9, acting as an inhibitory binding protein.
• GRP94 depletion significantly enhanced PCSK9's capacity to induce LDLR degradation without affecting ER homeostasis or PCSK9 secretion.
• Hepatocyte-specific Grp94-deficient mice exhibited elevated plasma LDLc and a substantial reduction in hepatic LDLR protein.

Conclusions:

• GRP94 plays a critical role in protecting LDLR from degradation by PCSK9 within the ER.
• Binding of PCSK9 to GRP94 likely prevents premature interaction with LDLR, thereby maintaining LDLR levels.
• This interaction represents a novel regulatory mechanism controlling cholesterol homeostasis and vascular health.