Plasmin inhibition by bacterial serpin: Implications in gum disease

Abstract

Tannerella forsythia is a periodontopathogen that expresses miropin, a protease inhibitor in the serpin superfamily. In this study, we show that miropin is also a specific and efficient inhibitor of plasmin; thus, it represents the first proteinaceous plasmin inhibitor of prokaryotic origin described to date. Miropin inhibits plasmin through the formation of a stable covalent complex triggered by cleavage of the Lys 368 -Thr 369 (P2-P1) reactive site bond with a stoichiometry of inhibition of 3.8 and an association rate constant (k ass ) of 3.3 × 10 5 M −1 s −1 . The inhibition of the fibrinolytic activity of plasmin was nearly as effective as that exerted by α 2 -antiplasmin. Miropin also acted in vivo by reducing blood loss in a mice tail bleeding assay. Importantly, intact T. forsythia cells or outer membrane vesicles, both of which carry surface-associated miropin, strongly inhibited plasmin. In intact bacterial cells, the antiplasmin activity of miropin protects envelope proteins from plasmin-mediated degradation. In summary, in the environment of periodontal pockets, which are bathed in gingival crevicular fluid consisting of 70% of blood plasma, an abundance of T. forsythia in the bacterial biofilm can cause local inhibition of fibrinolysis, which could have possible deleterious effects on the tooth-supporting structures of the periodontium. K E Y W O R D Sfibrinolysis, plasmin, periodontitis, serpin, Tannerella forsythia 620 |

A Comprehensive Phylogenetic Analysis of the Serpin Superfamily

“…Some bacterial serpins appear to play a role in host–commensal or host–pathogen interaction. Miropin, for example, has recently been demonstrated to efficiently inhibit human plasmin, thereby protecting invading T. forsythia cells from plasmin-mediated degradation and attenuating fibrinolysis in the pathogen’s local environment ( Sochaj-Gregorczyk et al. 2020 ).…”

The Serpin Superfamily and Their Role in the Regulation and Dysfunction of Serine Protease Activity in COPD and Other Chronic Lung Diseases

“…For example, a viral serpin, CrmA, can inhibit caspase-1 [25], and SERPINB3 can inhibit papain-like cysteine proteases cathepsins S, K and L [26]. The prokaryotic serpin, miropin, has also been identified as an inhibitor of a broad range of serine proteases, including neutrophil and pancreatic elastases, cathepsin G, plasmin, trypsin, subtilisin as well as the cysteine proteases cathepsin L and papain [27][28][29]. Additionally, a number of serpins can regulate biological functions without exhibiting any inhibitory activity, such as the regulation of hormone transport and blood pressure [30].…”

Gut Serpinome: Emerging Evidence in IBD

“…Recent reports indicate that miropin expression levels correlate with gingipain expression, encoded by P. gingivalis [ 132 ]. Moreover, miropin efficiently inhibits human plasmin, thereby enabling the bacterium to resist plasmin-mediated fibrinolysis and allow bacterial survival in pathological conditions [ 133 ]. Hence, miropin was suggested to mediate bacterial virulence and confer protection against both endogenous and exogenous proteases [ 131 , 133 ].…”