In a crucial step toward understanding the mechanisms involved in cardiovascular disease and certain types of cancer, a Canadian-led research team has succeeded in a world first: They have discovered the molecular mechanism by which the PCSK9 protein degrades low-density lipoprotein receptors, which are the richest. Cholesterol particles in the bloodstream.
The discovery, made by Nabil Sideh, director of the Biochemical Neuroendocrinology Research Unit at the Montreal Institute for Clinical Research and professor of medicine at the University of Montreal, is published in the January issue of Molecular metabolism.
His work was done in collaboration with Carole Frochart-Gaillard and colleagues in the Department of Pharmaceuticals and Health Technologies of the University Paris-Saclay, as well as with scientists in the Department of Pharmacology of the University of Pisa, Italy.
LDL can build up in the blood and lead to atherosclerosis and heart disease. The level of LDL and related cholesterol (LDLc) is directly modulated by the ability of the LDL receptor (LDLR) to collect LDL from the bloodstream and absorb it, primarily into hepatocytes. Surface LDLR directs the LDL to the cell where it is captured, and the LDLR returns to the surface for another round of capture.
Rare cases associated with the PCSK9 protein
Most cases of familial hypercholesterolemia are associated with LDLR abnormalities. But rare cases have been linked to the PCSK9 protein, which was discovered by the Sidon lab in 2003. PCSK9 is also present in the bloodstream where it binds to LDLR and promotes its degradation by liver cells, preventing it from returning to the surface to capture LDL. Some hypercholesterolemic patients have “super PCSK9” which promotes LDLR degradation.
In recent years, highly effective therapies have been made available to patients that either inhibit the function (called monoclonal antibodies) or reduce the level (called RNAi) of PCSK9 in the bloodstream, leading to higher amounts of LDLR that ensure a decrease in LDLc of more than 60 percent. Compared to traditional statins.
Now Seda and his team’s work lifts the veil on the previously misunderstood mechanism by which PCSK9 pulls LDLR toward lysosomes, where cells degrade the PCSK9-LDLR complex.
A complex of three partner proteins
In their lab, Seda and his team performed structural analyzes that revealed complex formation of three PCSK9 partner proteins, including LDLR, CAP1, and HLA-C.
A key protein in the immune system, HLA-C has been found to play an important role: it directs the entire complex to lysosomes. HLA-C allows for ‘self’ recognition, and it also stimulates the antitumor activity of T lymphocytes.
PCSK9, for its part, helps protect against the growth of tumors and associated metastases by increasing the level of HLA-C on the cell surface.
Ultimately, the hope is that inhibitors can be developed that block the interaction of PCSK9 and HLA-C and block the function of PCSK9 on LDLR and HLA-C.
This breakthrough can then be applied in clinical practice to treat cardiovascular diseases as well as various types of cancer and metastases in patients.
Gillard, C.F., et al. (2023) Molecular interactions of PCSK9 with inhibitory nanobody, CAP1 and HLA-C: functional regulation of LDLR levels. Molecular metabolism. doi.org/10.1016/j.molmet.2022.101662.