New findings reveal the previously misunderstood mechanism by which PCSK9 degrades the low-density lipoprotein receptor.
Investigators have made a major step toward understanding some cancers and cardiovascular disease, with the discovery of a molecular mechanism by which the protein PCSK9 degrades the receptor of low-density lipoproteins (LDL).
LDLs are the richest cholesterol particles in the bloodstream and can accumulate in the blood, leading to atherosclerosis and heart disease. The level of LDL and the cholesterol associated with it is directly modulated by the ability of LDL receptors to collect it from the bloodstream and internalize it, primarily into liver cells. Once LDL is captured in these cells, the receptors return to the surface for another round of capturing these proteins.
These findings could lead to breakthroughs for some types of cancer and cardiovascular pathologies, as well as some cases of familial hypercholesterolemia. Although most cases of familial hypercholesterolemia are related to LDL receptor dysfunction, rare cases have been linked to the PCSK9 protein, which was discovered in 2003 by the same research team who conducted this newer research.
PCSK9 is also present in the bloodstream, where it associates with the LDL receptors and promotes its degradation by liver cells, preventing them from returning to the surface to capture LDL. Some patients with hypercholesterolemia have a “super PCSK9,” which enhances the degradation of these receptors.
In recent years, highly effective new treatments have become available for patients. These include monoclonal antibodies that inhibit the function of PCSK9, as well as RNA interference drugs that reduce the level of PCSK9 in the bloodstream. Both of these treatment options result in larger amounts of LDL receptors, ensuring a decrease in LDL cholesterol of more than 60% compared with conventional statins.
Now, the new findings reveal the previously misunderstood mechanism by which PCSK9 drags the LDL receptors toward the lysosomes, where cells degrade the PCSK9-LDL receptor complex, according to the study authors.
In his lab, researcher Nabil G. Seidah, PhD, and his colleagues conducted structural analyses that revealed the formation of a complex of 3 PCSK9 partner proteins, including the LDL receptors, CAP1, and HLA-C. HLA-C was found to play a very important role, directing the entire complex toward the lysosomes.
It also stimulates the anti-tumor activity of T lymphocytes, according to the study. Further, PCSK9 is known to help protect against tumor growth and associated metastasis by increasing the level of HLA-C on the cell surface.
With this knowledge and new understanding of the mechanisms, the investigators hope that inhibitors can be developed that would prevent the interaction of PCSK9 and HLA-C, and block the function of PCSK9 on LDL receptors and HLA-C. That breakthrough could then be applied in clinical practice to treat cardiovascular pathologies, some cancers, and their metastases.
Better understanding cancer and heart disease. News release. University of Montreal; January 19, 2023. Accessed January 23, 2023. https://nouvelles.umontreal.ca/en/article/2023/01/19/better-understanding-cancer-and-heart-disease/