The Multifaceted Biology of PCSK9

Abstract

This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating low-density lipoprotein (LDL)-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain, its binding to the secreted cytosolic cyclase associated protein 1, and possibly another membrane-bound "protein X". Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the antitumoral activity of CD8+ T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors that reduces by 50% to 60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 monoclonal antibody or small interfering RNA could be added to current immunotherapies in cancer/metastasis.

Keywords: cancer/metastases; hypercholesterolemia; major histocompatibility complex I; sepsis; β-cells.

Graphical Abstract

By modulating the trafficking of key secretory proteins, PCSK9 is implicated in the regulation of major diseases. Secreted PCSK9 shortens the half-life of cell surface receptors, such as LDLR and MHC-I, by escorting them into the lysosomal pathway. The functional consequences of PCSK9 activity in different diseases is indicated.

Figure 1.

Schematic of PCSK9 and its potential partners. PCSK9 undergoes an autocatalytic cleavage between its catalytic and N-terminal prodomains, but the latter remains associated to the protein that has no other substrates. The C-terminal domain, CHRD, is composed of 3 tandem repeats (M1, M2, and M3) rich in Cys and His residues (Cys/His-rich domain). The LDLR binds the catalytic domain of PCSK9, while the MHC-I complex interacts with the M2 repeat of the CHRD. On the other hand, CAP1 binds the M1 and M3 domains of the CHRD and enhances PCSK9 activity.

Figure 2.

PCSK9 inhibition. Monoclonal Abs and siRNAs are safe and temporary inhibitors of PCSK9. Irreversible inhibition may be achieved through vaccination or PCSK9 gene modification via CRISPR-Cas. Finally, a more affordable inhibition based on orally active inhibitors is in development. See text for references.