Furin‐mediated protein processing in infectious diseases and cancer

Abstract

Proteolytic cleavage regulates numerous processes in health and disease. One key player is the ubiquitously expressed serine protease furin, which cleaves a plethora of proteins at polybasic recognition motifs. Mammalian substrates of furin include cytokines, hormones, growth factors and receptors. Thus, it is not surprising that aberrant furin activity is associated with a variety of disorders including cancer. Furthermore, the enzymatic activity of furin is exploited by numerous viral and bacterial pathogens, thereby enhancing their virulence and spread. In this review, we describe the physiological and pathophysiological substrates of furin and discuss how dysregulation of a simple proteolytic cleavage event may promote infectious diseases and cancer. One major focus is the role of furin in viral glycoprotein maturation and pathogenicity. We also outline cellular mechanisms regulating the expression and activation of furin and summarise current approaches that target this protease for therapeutic intervention.

The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

“…Strikingly, the 2019-nCoV S-protein sequence contains 12 additional nucleotides upstream of the single Arg↓ cleavage site 1 (Figs. 1B and 2) leading to a predictively solventexposed PRRAR↓SV sequence, which corresponds to a canonical furinlike cleavage site (Braun and Sauter, 2019;Izaguirre, 2019;Seidah and Prat, 2012). This furin-like cleavage site, is supposed to be cleaved during virus egress (Mille and Whittaker, 2014) for S-protein "priming" and may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b betacoronaviruses.…”

“…Indeed, it was recently shown that in an effort to limit viral infections, host cells that are infected by a number of viruses provoke an interferon response to inhibit the enzymatic activity of furin-like enzymes. It was also demonstrated that HIV infection induces the expression of either the protease activated receptor 1 (PAR1) (Kim et al, 2015) or guanylate binding proteins 2 and 5 (GBP2,5) (Braun and Sauter, 2019) that restrict the trafficking of furin to the trans Golgi network (PAR1) or to early Golgi compartments (GBP2,5) where the proprotein convertase remains inactive. Altogether, these observations suggest that inhibitors of furin-like enzymes may contribute to inhibiting virus propagation.…”

“…Furthermore the insertion of a multibasic motif RERRRKKR↓GL at the H5N1 hemagglutinin HA cleavage site was likely associated with the hyper-virulence of the virus during the Hong Kong 1997 outbreak (Claas et al, 1998). This motif exhibits the critical Arg at P1 and basic residues at P2 and P4, as well as P6 and P8 and an aliphatic Leu at P2' positions (Table 1) (Schechter and Berger nomenclature (Schechter and Berger, 1968)), typical of a furin-like cleavage specificity (Braun and Sauter, 2019;Izaguirre, 2019;Seidah and Prat, 2012).…”

A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin

“…Genomic analysis of the new CoV has shown that its SP differs from that of other viruses (Du et al, 2017;Li, 2016), indicating that the protein has a site activated by a HC enzyme called furin (Millet & Whittaker, 2015) (Figure 1). This enzyme normally cleaves and activates a wide range of substrates in different organisms (Figure 2a) (Braun & Sauter, 2019). This enzyme is found in many human tissues, including the lungs, liver and small intestine, which means that the virus has the potential to invade different organs (Belouzard et al, 2012;Heald-Sargent & Gallagher, 2012;Scamuffa et al, 2006).…”

Frontiers in antiviral therapy and immunotherapy

“…Here, Braun and Sauter review the roles of furin in these processes, as well as the history and future of furin-targeting therapeutics. 7 They also discuss their recent work revealing how two IFN-cinducible factors exhibit broad-spectrum inhibition of IAV, measles (MV), zika (ZikV) and HIV by suppressing furin activity. 8 Over the coming decade, I expect to see an ever-finer spatiotemporal resolution of host-oriented therapies to achieve safe, effective and broad-spectrum yet costeffective therapies for clinical use.…”