Furin at the cutting edge: From protein traffic to embryogenesis and disease

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Abstract
Furin is a ubiquitous proprotein convertase that cleaves substrates at the consensus sequence –Arg–X–Lys/Arg–Arg↓–. In exceptional cases, –Lys/Arg–X–X–X–Lys/Arg–Arg↓– is cleaved. Furin has greater than 50% activity at pH 5–8 and, like other subtilisin superfamily serine endoproteases, is strictly calcium dependent. The prodomain of furin is an intramolecular chaperone that guides enzyme folding and activation. Furin exploits its own cleavage-site rules to cut the prodomain twice during activation — first, at neutral pH in the endoplasmic reticulum at a consensus furin site, and second, after the pH-sensitive furin site –Arg70–Gly–Val–Thr–Lys–Arg75↓– in the mildly acidic trans-Golgi network (TGN)/endosomal system. Furin localizes to the TGN and follows a highly regulated trafficking itinerary through TGN/endosomal compartments and the cell surface, an itinerary that enables it to activate diverse proproteins in vivo. Furin's itinerary is controlled by the interaction between trafficking motifs in its cytoplasmic domain and sorting proteins. The casein kinase 2-phosphorylated acidic cluster binds to phosphofurin acidic cluster sorting protein-1, which links furin to adaptor protein (AP)-1 and directs retrieval to the TGN. The protein phosphatase 2A-dephosphorylated acidic cluster controls endosomal sorting. Basolateral targeting of furin is controlled by AP-4, and furin endocytosis is directed by AP-2. Cell-surface furin is tethered by the actin-binding protein filamin. Furin has fundamental roles in embryogenesis, homeostasis and disease. Processing of pro-β-nerve growth factor (NGF) controls whether the neurotrophin activates cell-survival or cell-death pathways. Furin's role in the secretase-mediated processing of amyloid precursor protein (APP) helps determine whether APP peptides enhance NGF signalling or cause neurodegeneration. Furin also controls the signalling range of tumour necrosis factor-α and transforming growth factor (TGF)-β family members. Although TGF-β activation by furin is essential for embryogenesis, this pathway exacerbates rheumatoid arthritis in adults. Furin is upregulated in several cancers, and increased furin levels correlate with increased levels of several of its processed substrates, including membrane-type-1 matrix metalloproteinase, insulin-like growth factor-1 and its receptor IGF-1R, and with greater tumour aggressiveness. Furin activates numerous bacterial toxins and pathogenic viruses. For example, cell-surface furin activates anthrax toxin, and early endosomal furin activates several A/B type toxins, including Pseudomonas exotoxin A, shiga toxin and diphtheria toxins. Many pathogenic viruses, including avian influenza virus, HIV-1 and measles virus, express envelope glycoproteins that require processing at consensus furin sites to form mature, fusogenic molecules. Additionally, the virulence of many deadly viruses, including Ebola virus, is directly correlated with the ability of the virus to incorporate a consensus furin cleavage site within its envelope proteins. Inhibition of furin blocks both pathogen activation and tumour metastasis.

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