How does mutant proprotein convertase neural apoptosis-regulated convertase 1 induce autosomal dominant hypercholesterolemia?

In the secretory pathway of the cell, many biologically inactive precursor proteins are processed by limited proteolysis to produce biologically active peptides and proteins. The enzymes that perform these cleavages are referred to as subtilisin-like proprotein convertases (SPCs).1 Seven members of the SPC family are known. One, the subtilisin kexin isoenzyme-1/site-1-protease (SKI-1/S1P), has a key role in cholesterol homeostasis through processing of the sterol regulatory element-binding proteins (SREBPs).2,3 Another member of the SPC family, neural apoptosisregulated convertase 1 (NARC-1), which was recently linked to a novel form of autosomal dominant familial hypercholesterolemia,4 is downregulated by cholesterol and upregulated by SREBP-2.5,6 These findings indicate that NARC-1, like SKI-1/S1P, is an important player in lipid metabolism.