Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

Furin may not only promote disease upon aberrant expression, but also by activating a variety of pathogen-derived proteins. One example for cleavage of unwanted proteins is the proteolytic activation of bacterial toxins. Particularly, the group of AB toxins comprises several well-described furin substrates. These exotoxins are secreted by bacteria and exert their effect in the cytoplasm of the target cell. They usually consist of an enzymatically active A subunit and a B subunit that mediates membrane binding and translocation. To exert its toxic effect, the A subunit has to be separated from the membrane-associated B subunit by proteolytic cleavage. 39 In case of diphtheria toxin and Pseudomonas exotoxin A, furin cleaves R-V-R-R↓ and R-Q-P-R↓ target sequences, respectively. 40, 41 Cleavage most likely occurs in endosomes before the A subunit translocates into the nucleus where it inhibits protein synthesis by inhibiting the elongation factor eEF2. 42 In line with an important role of furin in bacterial virulence, toxicity is highest if an optimal furin cleavage site is present. 43 Similarly, furin cleaves Shiga and Shiga-like toxins expressed by certain Shigella spp. and Escherichia coli strains and enhances their ability to halt protein synthesis. Although a furin target sequence is conserved among all Shiga-like toxins, mutational analyses suggested that furin-mediated cleavage augments toxin activity, but is not essential. 39 Another wellcharacterised example is anthrax toxin, a threeprotein exotoxin consisting of the receptor binding protective antigen (PA) and the enzymatically active components oedema factor (EF) and lethal factor (LF). Upon binding to its receptor, PA is cleaved by furin at the cell surface. This cleavage step triggers the oligomerisation of PA into a prepore that binds EF and LF. Subsequently, this toxin complex is endocytosed and PA forms a channel that allows the translocation of EF and LF into the cytoplasm. 39 Although PA can be activated by different proprotein convertase family members, furin seems to be the major protease activating anthrax toxin. 44 These examples illustrate that several bacterial pathogens exploit furin and related convertases for the activation of their exotoxins. Strictly speaking, however, some toxins produced by bacteria (e.g. diphtheria toxin and Shiga toxins) represent viral gene products as they are encoded by bacteriophages. 45 In these cases, the term 'viral exotoxin' may be more appropriate. This strongly suggests that furin-mediated toxin activation confers a selection advantage to both, the bacterium and its phage. For example, induction of cell death by furin-activated toxins may promote tissue invasion, increase transmission rates (e.g. by causing diarrhoea) or suppress cellular immune responses. Without the proteolytic activation of exotoxins, diseases such as dysentery or diphtheria would not occur.