We are interested in the elucidation at the molecular, cellular and in vivo levels of the mechanisms of the biosynthetic machinery and its components that are critical for the intracellular and extracellular processing and maturation of secretory proteins, prohormones and zymogens in general. Such proteolytic processing resulting in activation or inactivation of proteins, mostly occurs at the C-terminus of either single or paired basic amino acids but also at non basic residues. The 9 proprotein convertases known that we recently cloned and/or extensively characterized are: PC1, PC2, Furin, PC4, PACE4, PC5, PC7 as well as SKI-1 and PCSK9. We are elucidating the implication of these convertases in disease states and pathologies such as cancer, neurodegenerative diseases, viral infections, and dyslipidemia such as atherosclerosis and hyperholesterolemia both in human and in animal models. Thus, we have shown that the convertases SKI-1 and PCSK9 play major roles in the metabolism and/or synthesis of cholesterol and fatty acids. The development of knockout and transgenic mice with loss or gain of function of some convertases allowed us to better define their in vivo functions in normal and disease states. We have recently identified specific ways to inhibit these enzymes leading the way to clinical applications in pathologies, especially for PCSK9 in the treatment of hypercholesterolemia.