Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protease that acts as a regulator of circulating plasma cholesterol levels by enhancing the endocytosis of the low density lipoprotein receptor (LDL‐R) at the cell surface of hepatocytes. In this study, we show that overexpression of PCSK9's prodomain reduces the secretion of its mature form, as measured by a newly developed PCSK9‐luciferase assay. Similarly, treatment of cells with the non‐specific permeable serine protease inhibitor pefabloc decreases the secretion of mature PCSK9. We show by overexpression and immunoprecipitation that the prodomain is interchangeable on the catalytic domain of PCSK9. Medium from PCSK9‐transfected CHO cells overexpressing the prodomain or treated by pefabloc leads to enhanced surface LDL‐R expression in hepatic cells in contrast to medium from PCSK9‐transfected CHO cells only, demonstrating the functional consequences of both modes of inhibition.
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