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.

Keywords: bacterial toxins; cancer; furin; guanylate‐binding proteins; proprotein convertases; viral glycoproteins.

Figure 1

Furin cleaves and activates a variety of mammalian, viral and bacterial substrates. The serine protease furin is essential for proper activation of a variety of cellular precursor proteins. As a consequence, aberrant expression or activity of furin may result in a variety of disorders (left panel). Furthermore, numerous viruses exploit furin for the activation of their glycoproteins (central panel) and several bacterial exotoxins are activated by furin‐mediated cleavage (right panel). E2, glycoprotein E2; Env, envelope; F, fusion protein; gB, glycoprotein B; GP, glycoprotein; HA, hemagglutinin; PreGn, precursor glycoprotein Gn; prM, premembrane protein; S, spike protein.

Figure 2

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.

Figure 3

Furin‐mediated processing of viral proteins can occur at several steps of the viral replication cycle. While some viral proteins are proteolytically processed during maturation or egress (a), others are cleaved during entry into new target cells (b). (a) In case of the human immunodeficiency virus (HIV) (left panel), the viral envelope (Env) glycoprotein precursor (green) migrates through the ER to the Golgi complex where it is cleaved by furin (pink scissors) into the functional mature Env glycoprotein (blue). Processed Env glycoproteins are transported to the cell surface and incorporated into assembling viral particles. In contrast, dengue viruses bud into the ER lumen and incorporate the uncleaved premembrane protein (prM) (right panel). During virus particle transit through the secretory pathway, virion‐associated prM proteins can be cleaved by furin (dark blue to light blue). (b) Some prM molecules escape furin‐mediated cleavage in the producer cells resulting in the release of immature or partially mature dengue virus particles. In this case, processing can also occur in endosomes of new target cells, upon receptor‐mediated endocytosis (left panel). During human papillomavirus (HPV) infection (right panel), attachment to heparan sulphate proteoglycans induces a conformational change that allows proteolytic processing of the minor capsid protein L2 (red) by furin, which is present at the cell surface. Furin processing induces a structural rearrangement that allows binding to a secondary receptor and subsequent receptor‐mediated endocytosis.

Figure 4

PAR1 as well as GBP2 and GBP5 reduces HIV particle infectivity by inhibiting furin‐mediated Env processing. Human immunodeficiency virus (HIV) particles containing functional mature envelope (Env) glycoproteins fuse with the plasma membrane of the target cell to release the capsid core into the host cell cytoplasm. Upon reverse transcription and integration of the retroviral genome, viral gene expression is initiated. (a) In a cytokine (e.g. IL‐1β)‐induced inflammatory state, furin and protease‐activated receptor 1 (PAR1) expression are induced. Furin and PAR1 interact with each other and are trapped as inactive proteins in the trans‐Golgi network (TGN). As a consequence, PAR1 cannot traffic to the cell surface, where it is usually cleaved by thrombin to induce inflammatory signalling pathways. Moreover, production of infectious HIV‐1 particles is impaired because of reduced furin‐mediated cleavage of HIV Env. (b) At the same time, cells of the infected host may induce the expression of interferon‐stimulated genes such as guanylate‐binding proteins 2 and 5 (GBP2 and GBP5). Both proteins colocalise with furin and inhibit its proteolytic activity. As a result, HIV Env maturation is impaired and newly forming viral particles are poorly infectious since they incorporate immature Env glycoproteins. IFN‐I/II, type I and type II interferons; STAT, signal transducers and activators of transcription.