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PCSK9

Official Full Name
proprotein convertase subtilisin/kexin type 9
Organism
Homo sapiens
GeneID
255738
Background
This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
Synonyms
FH3; PC9; FHCL3; NARC1; LDLCQ1; NARC-1; HCHOLA3;
Bio Chemical Class
Peptidase
Protein Sequence
MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGTTATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLPGFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLVEVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAGVAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAACQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVDLFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSAKDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPDEELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAPPAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASCCHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRDVSTTGSTSEGAVTAVAICCRSRHLAQASQELQ
Open
Disease
Cardiovascular disease, Chronic obstructive pulmonary disease, Coronary atherosclerosis, Hyper-lipoproteinaemia, Hyper-lipoproteinaemia
Approved Drug
3 +
Clinical Trial Drug
14 +
Discontinued Drug
0

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Detailed Information

The PCSK9 gene, located at 1p32.3, encodes Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). After being synthesized in the liver, PCSK9 undergoes autocatalytic cleavage into its active form and is secreted into the bloodstream, where it binds to the low-density lipoprotein receptor (LDLR). PCSK9 interacts with the EGF-A domain of LDLR on the hepatocyte surface, forming a complex that is internalized into lysosomes, thereby preventing LDLR from recycling back to the cell membrane and reducing the clearance of LDL cholesterol (LDL-C).

Genetic studies reveal a dual role for PCSK9:

  • Gain-of-function mutations (e.g., D374Y): These mutations enhance the binding affinity between PCSK9 and LDLR, resulting in serum LDL-C levels exceeding 200 mg/dL and leading to familial hypercholesterolemia.
  • Loss-of-function mutations (e.g., R46L): These reduce LDLR degradation, lower LDL-C by approximately 28%, and significantly decrease the risk of coronary heart disease.

Beyond its classical role in lipid metabolism, PCSK9 also contributes to tumor metastasis by degrading low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 normally acts as a transcriptional repressor by binding to the promoters of metastasis-related genes such as XAF1 and USP18. When PCSK9 binds and degrades LRP1, this repression is lifted, leading to overactivation of metastasis-promoting genes.

Figure 1. PCSK9 and LDLR biology in liver hepatocytes. (Hummelgaard S, et al., 2023)

Cardiovascular Disease and Targeted Therapy

PCSK9 monoclonal antibodies have marked a milestone in lipid-lowering therapies over the past decade:

  • Potent LDL-C Reduction: Alirocumab, administered at 75 mg biweekly, reduces LDL-C by 50.6% after 24 weeks compared to only 20.7% with ezetimibe.
  • Cardiovascular Benefits: The ODYSSEY OUTCOMES trial, which included 18,924 patients with acute coronary syndrome, demonstrated a 15% reduction in major cardiovascular events and a 15% decrease in all-cause mortality with Alirocumab treatment.

A 2024 Cell study revealed a novel oncogenic mechanism of PCSK9. The common germline variant rs562556 (V474I), present in 70% of the European population, encodes a mutant protein with enhanced LRP1-degrading capacity. This removes repression of XAF1 and USP18, promoting metastasis. Among breast cancer patients homozygous for the mutation, the 15-year distant metastasis rate reaches 22%, a tenfold increase compared to non-carriers. In animal models, PCSK9 knockout reduces pulmonary metastases by 80%, and the monoclonal antibody Evolocumab mimics this effect.

Expanding Clinical Indications

Based on these findings, the therapeutic potential of PCSK9 inhibitors extends beyond cardiovascular disease:

  • Metastasis Prevention: In a Phase II clinical trial, Evolocumab treatment in breast cancer patients carrying the rs562556 variant prolonged median metastasis-free survival by 15 months.
  • Neuroprotection: PCSK9 promotes neuronal apoptosis via degradation of LRP8/APOER2. In Alzheimer's disease models, Evolocumab reduced amyloid-beta (Aβ) deposition by 40%.

Challenges and Future Outlook

Current limitations include:

  • Administration Route: Monoclonal antibodies require subcutaneous injection every 2–4 weeks. Although siRNA-based Inclisiran is administered only twice a year, its long-term safety remains under investigation.
  • Cost-Effectiveness: Annual treatment costs exceed $5,000, limiting accessibility in low- and middle-income countries.

Future strategies focus on personalized therapy. Screening for rs562556 mutations could guide preventive treatment in breast cancer. Dual-target therapies—such as combining PCSK9 inhibitors with PD-1 antibodies—show synergistic effects in hepatocellular carcinoma models. With the oral small-molecule inhibitor MK-0616 entering Phase III clinical trials, the accessibility of PCSK9-targeted treatments is expected to improve significantly.

References:

  1. Hummelgaard S, Vilstrup JP, Gustafsen C, et al. Targeting PCSK9 to tackle cardiovascular disease. Pharmacol Ther. 2023 Sep;249:108480.
  2. Roth EM, Davidson MH. PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety. Rev Cardiovasc Med. 2018;19(S1):S31-S46.
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