Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

The canonical furin cleavage site is frequently described as R-X-K/R-R↓. However, variations of this motif may also be recognised and a stretch of 20 amino acids surrounding the cleavage site as well as post-translational modifications determine interaction with the furin binding pocket. 21 Bioinformatic analyses and functional studies uncovered more than 100 furin cleavage sites in mammalian proteins. These comprise growth factors and cytokines (e.g. IGF1, IGF2, TGFb, PDGFa, PDGFb, VEGF-C, NGF, CXCL10), hormones (e.g. PTH, TRH, GHRH), adhesion molecules (e.g. integrins, vitronectin), collagens, metalloproteinases, coagulation factors, receptors, membrane channels and albumin. 2 While most of these target factors are activated upon furin-mediated cleavage, furin also exerts inactivating cleavage steps. For example, the furin paralogue PCSK9 and endothelial lipase can be inactivated by furin. 22 Maturation of the cellular protease furin. Furin expression is driven by three different promoters, sharing characteristics of either cytokine-activated (P1) or housekeeping gene (P1A and P1B) promoters. During translation, furin is integrated into ER membranes and glycosylated. After the N-terminal signal peptide (red) is removed, an autocatalytic cleavage event occurs, generating a short propeptide (light blue). This propeptide remains associated with furin and acts as an intramolecular chaperone and inhibitor. After transit to the Golgi complex, the propeptide is removed and glycans are trimmed before furin gains its proteolytic activity. Furin accumulates in the trans-Golgi network (TGN), but can also traffic to the plasma membrane and cycle between these two compartments via endosomes. Proteolytic cleavage at the C terminus of furin separates the transmembrane domain (orange) from the catalytically active domain. As a result, furin can be shed into the extracellular space as an active enzyme.