Table 1.
Pla interactions with different substrates.
| Substrates | Biological Function/Process | Hydrolyzable Amino Acids of Substrate | Consequence | Proven or Not Substrate In Vivo | Contribution to Virulence/Pathogenesis | References |
|---|---|---|---|---|---|---|
| Host proteins processed by Pla | ||||||
| Peroxiredoxin 6 (Prdx6) | Immune system process; ROS metabolic process | Cleaves at sites Lis173/Arg174, Lys201/Leu202, and the undefined site located in the C-terminal region | Disrupt peroxidase and phospholipase A2 activities | yes | The cleavage of Prdx6 has a little detectable impact on the progression or outcome of pneumonic plague | [66] |
| Alpha2-antiplasmin (A2AP) | proteolysis; contributes to control of the pulmonary inflammatory response to infection by reducing neutrophil recruitment and cytokine production | ND | uncontrolled production of active plasmin and resulting clearance of fibrin depositions | no | A2AP is not significantly affected by the Pla protease during pneumonic plague; A2AP participating in immune modulation in the lungs has a limited impact on the course or ultimate outcome of the infection | [65,66,82] |
| Plasminogen activator inhibitor-1 (PAI-1) | inhibition of activation of plasminogen. | cleaves between residues R346 and M347 | prevent inhibition of tPA and uPA | yes | PAI-1 deficiency results in a decreased level of neutrophil influx to the pulmonary compartment during pneumonia. This leads to increased bacterial out-growth, enhanced dissemination, and decreased survival of infected mice | [66,82] |
| Urokinase plasminogen activator (uPA) | activation of plasminogen | cleaves the single-chain uPA (scuPA) between residues Lys158 and Ile159 | cleavage led to the activation of scuPA | no | activates fibrinolysis, cell migration, and tissue remodeling | [61,66] |
| Complement component C3 | cytokine activity; complement activation | ND 1 | ND | no | cleavage of C3 disrupts chemotaxis of inflammatory cells to foci of infection, leads to disturbances in their phagocytic activity and the inability of the complement system to form the cytolytic end product of the complement system activation, membrane attack complex | [66,82] |
| Apoptotic molecule Fas ligand (FasL) | immune system process; its binding with its receptor induces apoptosis | cleaves at multiple sites located within the extracellular domain of FasL | ND | no | contribute to the progression of pneumonic plague | [66] |
| Glutathione S-transferase A3 | immune system process; ROS metabolic process | ND | ND | no | ND | [66] |
| Glutathione peroxidase 3 | immune system process; response to toxin | ND | ND | no | ND | [66] |
| Tubulin polymerization-promoting protein family | cell component; structure | ND | ND | no | ND | [66] |
| Pigment epithelium-derived factor | protein binding; proteolysis | ND | ND | no | ND | [66] |
| Alpha-2-HS-glycoprotein | protein binding; immune system process; proteolysis | ND | ND | no | ND | [66] |
| Glutathione S-transferase Mu 1 | immune system process; transferase activity | ND | ND | no | ND | [66] |
| BPI fold-containing family A member 1 (sPlunc) | immune system response | ND | ND | no | ND | [66] |
| Carboxypeptidase N subunit 2 | immune system process; cytokine-mediated signaling | ND | ND | no | ND | [66] |
| Sulfated glycoprotein 1 | protein binding; lipid transport | ND | ND | no | ND | [66] |
| BPI fold-containing family b member 1 (Lplunc1) | MAC activation, response to stress | ND | ND | no | ND | [66] |
| Vinculin | actin binding; cell adhesion | ND | ND | no | ND | [66] |
| Plasminogen | serine-type peptidase activity; proteolysis | cleavage at a single site between residues Arg561 and Val562 of the proenzyme | activates plasminogen through cleavage this zymogen at a single site | no | activates fibrinolysis | [66,82] |
| Actin gamma | cell component; structure | ND | ND | no | ND | [66] |
| Plastin-2 | structure; actin binding | ND | ND | no | ND | [66] |
| Lipoprotein lipase | lipase activity; lipid transport | ND | ND | no | ND | [66] |
| Phosphoglycerate mutase 1 | glycolysis | ND | ND | no | ND | [66] |
| Complement C4-B | complement activation; signal transduction | ND | ND | no | ND | [66] |
| Hypoxanthine-guanine phosphoribosyltransferase | monosaccharide metabolic process | ND | ND | no | ND | [66] |
| Calmodulin | Ca2+ binding | ND | ND | no | ND | [66] |
| Apolipoprotein A-IV | lipid transporter activity; blood circulation | ND | ND | no | ND | [66] |
| Thrombin-activatable fibrinolysis inhibitor (TAFI) | antifibrinolytic plasma protein | ND | Pla can cleave TAFI near its C-terminus, preventing activation to TAFIa during subsequent incubation with thrombin–thrombomodulin; in addition to the direct inactivation of TAFI by Pla, TAFIa can also be inactivated through proteolysis by plasmin | yes | ND | [82] |
| Tissue factor pathway inhibitor (TFPI) | TFPI is an anticoagulant protein that reversibly binds to coagulation factor Xa (FXa). This bimolecular TFPI–FXa complex is a potent inhibitor of the procoagulant complex TF:FVIIa (the primary initiator of coagulation in vivo), which acts to block further coagulation at this point in the cascade | Cleavage of TFPI by Pla occurs between residues K249 and G250 | cleavage by Pla is predicted to have procoagulant consequences; Pla disrupts the TFPI-mediated inhibition of clot formation | no | TFPI inactivation enhances coagulation | [82] |
| Cathelicidins | cationic antimicrobial peptides (CAMPs) | CAMPs permeabilize bacterial lipid bilayers, resulting in the lysis of affected cells; Pla inhibit CAMPs chemoattractant properties that recruit neutrophils, monocytes, and T cells in response to infection | no | ND | [82] | |
| α-2-macroglobuline | impede the plasmin activity | ND | ND | no | activates proteolysis | [28] |
| Y. pestis proteins processed by Pla | ||||||
| Type-III secretion system effectors | inhibit phagocytosis, induce apoptosis of macrophages, destroy actin cytoskeleton and signaling pathway of activation of inflammatory cells, suppress production of cytokines and chemokines | ND | degrades most Yops in vitro including the Yops B, C, D, E, F, H, J, and M, but is unable to degrade LcrV | no | it is supposed that Pla coordinates the degradation of extracellular Yops that may otherwise compromise innate immunity evasion | [14,82] |
| YapA | autotransporter | processes at multiple sites (Lys512, Lys548/Lys549, Lys594/Lys595, Lys558, and Lys604) | cleavage at the C terminus released the protein from the cell surface | no | it is supposed that YapA might be an adhesin | [83] |
| YapG | autotransporter | processes at multiple sites | ND | no | does not contribute to Y. pestis virulence in established mouse models of bubonic and pneumonic infection | [81] |
| YapE | autotransporter | processes at two sites (Lys232 and Lys338 but preferentially at Lys232) | cleavage is required to proteolytical activation of the protein | no | contributes to disease in the mouse model of bubonic plague by mediating bacterial aggregation and adherence to eukaryotic cells | [84] |
| KatY | catalase-peroxidase | Cleavage of α-KatY (78.8 kDa) by Pla resulted in its smaller forms, β-KatY (∼50 kDa), γ-KatY (∼36 kDa) and δ-KatY (∼34 kDa) | ND | no | ND | [85] |
1 “ND”, no data.