Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

The prototypical and best-characterised member of the PCSK family is furin/PCSK3. Since it cleaves basic amino acid motifs, it has also been termed PACE (paired basic amino acid cleaving enzyme). Furin is expressed by the FUR (FES upstream region) gene on chromosome 15. Although furin is ubiquitously expressed, its mRNA and protein levels vary depending on the cell type and tissue. High levels can be found in salivary glands, liver and bone marrow, whereas muscle cells express relatively low amounts of furin. 9 Three promoters (P1, P1A and P1B), each harbouring an alternative transcription start site, have been described ( Figure 2 ). However, the respective transcripts differ only in the first untranslated exon and are therefore predicted to express the same protein. 10 While the P1A and P1B promoters resemble those of constitutively expressed housekeeping genes, the P1 promoter binds the transcription factor C/EBPb and can be trans-activated upon cytokine stimulation. 10 In line with this, IFNc, TGFb, IL-12 and PMA induce furin expression. [11] [12] [13] [14] Upon translation of the mRNA, furin enters the secretory pathway as an inactive proenzyme and is integrated into the ER membrane via its Cterminal transmembrane domain ( Figure 2 ). Like most type I transmembrane proteins, it harbours a short N-terminal signal peptide that is cleaved off cotranslationally. Similar to other proprotein convertases, furin contains an inhibitory Nterminal 83-amino acid propeptide, whose chaperone function is required for correct folding of the catalytic domain. 15 During the transition of furin from the ER to the trans-Golgi network (TGN), the inhibitory propeptide is removed in a two-step autoproteolytic process and furin gains its enzymatic activity. 16 At the same time, N-linked oligosaccharides are added and trimmed. Although furin accumulates in the TGN, it can be further transported to the cell surface and back via the endosomal pathway. 17, 18 Finally, furin can also be shed and released into the extracellular space upon proteolytic separation of the catalytic domain from the membrane-bound C terminus. 19 Whether this cleavage step is mediated by furin itself or another protease remains to be determined. 20 The presence of furin in the TGN and endosomal compartments, at the cell surface and in the extracellular space, may explain its ability to process a large variety of intra-and extracellular substrates.