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  • Enolase is an example of a

    2020-01-23

    Enolase is an example of a moonlighting protein that displays multiple biological actions, including plasminogen, laminin, fibronectin, mucin and cytokeratin binding properties. It has also been described as a complement-evasion protein and as a protein capable of inducing neutrophil trap formation. Spirochetes from the JIB-04 Borrelia and Leptospira have been shown to recruit host plasminogen through surface-exposed enolase [40], [17]. A recent study focusing on extracellular proteins identified enolase in culture supernatants of L. interrogans, thus indicating that this protein is also secreted by an as-yet-unknown mechanism [41]. Plasminogen activators convert the zymogen plasminogen into plasmin, the active protease that degrades diverse substrates. In the present study, we evaluated the functional consequences of plasminogen binding to Leptospira enolase. According to our data, enolase-bound plasminogen was converted to plasmin in the presence of host-derived uPA. As the coagulation cascade and complement molecules are among plasmin targets, we then assessed its capacity to degrade fibrinogen, vitronectin and the complement proteins C3b and C5. Plasmin bound to Leptospira enolase was able to completely degrade the β-chain of fibrinogen after 4 h of incubation. The degradation profile was similar to that observed for plasmin bound to EF-Tu, another moonlighting protein from Leptospira. Interestingly, under the same conditions, this protease degraded human vitronectin, a multifunctional adhesive glycoprotein found in serum and in the extracellular matrix. Fragments in the range of 61–63 kDa were generated upon incubation of enolase-bound plasminogen with vitronectin and uPA. Previous studies have shown that vitronectin proteolysis by plasmin produces well-defined cleavage products. Initial plasminolysis of vitronectin removes C-terminal residues of the molecule and generates 61–63 kDa fragments [42]. Curiously, these fragments lacking the C-terminus display about threefold higher efficiency in plasminogen binding compared to intact vitronectin. Late plasminolysis produces fragments in the range of 56–35 kDa which are not effective in promoting cell adhesion [42]. Thus, plasmin modification of vitronectin may play a key role in modulating cell–matrix interactions at specific sites, thereby contributing to invasive processes, including angiogenesis, as suggested by Kost and colleagues (1996), or bacterial infections. Other natural substrates for plasmin include complement proteins [37]. Degradation of both C3b and C5 by enolase-bound plasmin was assessed. However, non-specific fragments were produced, thus indicating that this process might not be physiologically relevant. Enolase can also function as an immune evasion protein by interacting with the negative complement regulator C4BP [23]. Once bound to a pathogen surface, C4BP may downregulate the classical and/or lectin pathway of complement by dissociating the C3 convertase and by acting as a cofactor for FI in cleavage of C4b. Reduced activation of the complement cascade prevents the pathogen from lysis. In this study, we identified enolase as an additional leptospiral C4BP binding protein. Interaction with FH, the main soluble regulator of the alternative pathway of complement, was also assessed. FH acts by dissociating the C3 convertase of the alternative pathway of complement and by serving as a cofactor of FI in cleavage of C3b. According to our data, Leptospira enolase also bound FH. C4BP and FH bound to enolase retained cofactor activity, as determined by C4b and C3b degradation. It is interesting to note that Streptococcus pneumonia enolase binds C4BP and plasminogen, but not FH, from human serum [23], unlike Leptospira enolase, which is capable of recruiting all three host molecules. It has been demonstrated that Borrelia burgdorferi, the Lyme disease spirochete, also recruits host plasminogen through surface-exposed enolase [40]. Plasminogen contributes to efficient dissemination in ticks and enhances spirochetemia in mice [43]. In conclusion, enolase, as a moonlighting protein, may facilitate spirochetal dissemination, thus contributing to bacterial virulence. The characterization of this multifunctional class of proteins is of great relevance, as they may represent potential future therapeutic targets for fighting bacterial infections.