The Multifaceted Biology of PCSK9

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 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 (CHRD), its binding to the secreted cytosolic cyclase associated protein 1 (CAP-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 anti-tumoral activity of CD8 + T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors (PCSK9i) that reduces by 50-60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 mAb or siRNA could be added to current immunotherapies in cancer/metastasis.