Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

Although PCSKs are frequently coexpressed in the same cell and may cleave the same substrates, there is no complete redundancy and the inactivation of individual PCSKs results in specific knock-out phenotypes in mice. 6 PCSK1-7 cleave their substrates after basic residues, with the typical recognition motif K/R-X n -K/R↓ 6 ( Table 1 ). In contrast, PCSK8 cleaves after nonbasic residues and is best known for its regulation of cholesterol and lipid metabolism by activating sterol regulatory element-binding protein (SREBP) transcription factors. 6, 7 Like PCSK8, PCSK9 also plays a key role in cholesterol metabolism as it regulates low-density lipoprotein (LDL) particle levels in the blood. However, this effect does not involve proteolytic cleavage of a specific substrate, but is mediated by a direct binding of PCSK9 to LDL receptors. 8 With two FDA-approved inhibitors for the treatment of hypercholesterolaemia, PCSK9 is also the prime example of a protease that is successfully targeted for therapy. 6