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Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon's knife to a meat chopper-like brutal degradation of proteins.

Arguably periodontitis is the most prevalent bacteria-driven chronic inflammatory disease of the humankind. The incidence of periodontal disease has been reported to range from 30% of the population in developed countries (154) to over 70% of the population in developing countries (198) with severe disease inflicting 7% to 15% of human population worldwide (41, 67, 154). Periodontitis is a major cause of loss of teeth, and is also implicated in the onset, development and/or progression of systemic diseases such as cardiovascular diseases (68), rheumatoid arthritis (27, 207, 224) and Alzheimer disease (87-89). 
 
The involvement of bacteria in the etiology of periodontitis is unquestionable but the composition of the causative species is still being debated. Presently, over 500 bacterial species have been detected in periodontal plaque (160) but only a handful, including Porphyromonas gingivalis has been implicated as major pathogens of chronic periodontitis (208), the most prevailing form of periodontal disease. This bacterium produces a variety of virulence factors including, bioactive metabolic products, fimbriae, and an array of proteolytic enzymes (107). Among the proteolytic enzymes, cysteine proteases referred to as gingipains are responsible for at least 85% of total proteolytic activity exerted by various strains of P. gingivalis (171) and are considered major contributors to the pathogenic potential of P. gingivalis. Indeed, three lines of evidence, including immunization, analysis of knockout strains, and testing of specific protease inhibitors using murine models of infection or bone loss clearly indicate that gingipains are absolutely essential for bacterial survival/proliferation in vivo and for the pathological outcome of the experimental infection (Table 1). 
 
 
 
Table 1 
 
Gingipains are essential virulence factor of P. gingivalis indispensable for pathological outcome of experimental infection. 
 
 
 
Gingipains, including arginine-specific gingipains (Arg-gingipain-A, RgpA and Arg-gingipain-B, RgpB) and lysine-specific gingipain (Lys-gingipain, Kgp), are encoded by three different genes referred to as rgpA, rgpB and kgp, which are conserved among laboratory and clinical strains of P. gingivalis (26). The rgpA and rgpB genes translation products, RgpA and RgpB, share a basically identical caspase-like protease domain with specificity restricted to Arg-Xaa peptide bonds and an Ig-like domain. In RgpA, the protease and the Ig-like domains are followed by a large C-terminal extension known as the hemagglutinin-adhesin domains. Similarly, the kgp gene translation product, Kgp, consists of a catalytic domain with selectivity for Lys-Xaa peptide bonds followed by a C-terminal extension similar to that in RgpA. Except for a short C-terminal domain shared with RgpA and Kgp and several other secretory proteins (136, 189), the hemagglutinin-adhesin domains are absent in RgpB. During the secretion process, progingipains are subjected to extensive posttranslational proteolytic processing and glycosylation. Finally, they are secreted either as a monomeric form (RgpB) or as a non-covalent but stable complexes of protease and hemagglutinin-adhesin domains (RgpA and Kgp), which are either predominantly attached to the bacterial surface or released into the medium in a soluble form depending on P. gingivalis strain (Fig. 1). The varied external localization of these multi-functional gingipain complexes makes them the perfect tool for manipulation of the host immune system by P. gingivalis. 
 
 
 
Fig. 1 
 
Schematic diagram of discrete steps in gingipain secretion, processing, posttranslational maturation, and assembly of extracellular gingipain complexes. Western blot analysis (upper corners) of the whole culture of P. gingivalis strain HG66 and W83 using ... 
 
 
 
In this review, we will discuss how gingipains participate in sequential phases of the disease process starting from (i) adherence and colonization, through (ii) nutrient acquisition, (iii) neutralization of host defenses and manipulation of inflammatory response, to (iv) tissue destruction, invasion and dissemination to systemic sites. Over the past 15 years, gingipains have been the subject of more than 20 reviews, including a few truly outstanding comprehensive compendiums on the role of these enzymes as virulence factors of P. gingivalis (35, 84, 193). Consequently, in this paper, we will focus on the most recent investigations and cite the previous reviews where appropriate. For references on the early work on the gingipains, we invite the reader to peruse reviews by Imamura (69, 73), Kadowaki & Yamamoto (84), Potempa and colleagues (169, 172), Nakayama (131), and O'Brien-Simpson and colleagues (144).