Division of Infection Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.
Université de Lorraine, CNRS, Inria, LORIA, Nancy, France.
Nat Commun. 2024 Nov 25;15(1):10212. doi: 10.1038/s41467-024-54173-6.
Group A Streptococcus (GAS) is a human-specific bacterial pathogen that can exploit the plasminogen-plasmin fibrinolysis system to dismantle blood clots and facilitate its spread and survival within the human host. In this study, we use affinity-enrichment mass spectrometry to decipher the host-pathogen protein-protein interaction between plasminogen and streptolysin O, a key cytolytic toxin produced by GAS. This interaction accelerates the conversion of plasminogen to plasmin by both the host tissue-type plasminogen activator and streptokinase, a bacterial plasminogen activator secreted by GAS. Integrative structural mass spectrometry analysis shows that the interaction induces local conformational shifts in plasminogen. These changes lead to the formation of a stabilised intermediate plasminogen-streptolysin O complex that becomes significantly more susceptible to proteolytic processing by plasminogen activators. Our findings reveal a conserved and moonlighting pathomechanistic function for streptolysin O that extends beyond its well-characterised cytolytic activity.
A 组链球菌（GAS）是一种特定于人类的细菌病原体，它可以利用纤溶酶原-纤溶纤维蛋白溶解系统来分解血栓，并促进其在人类宿主中的传播和存活。在这项研究中，我们使用亲和富集质谱法来破译纤溶酶原与链球菌溶血素 O 之间的宿主-病原体蛋白-蛋白相互作用，链球菌溶血素 O 是 GAS 产生的一种关键细胞溶解毒素。这种相互作用通过组织型纤溶酶原激活物和 GAS 分泌的细菌纤溶酶原激活物加速纤溶酶原向纤溶酶的转化。综合结构质谱分析表明，这种相互作用诱导纤溶酶原的局部构象变化。这些变化导致稳定的中间纤溶酶原-链球菌溶血素 O 复合物的形成，该复合物对纤溶酶原激活物的蛋白水解处理变得更加敏感。我们的研究结果揭示了链球菌溶血素 O 的一种保守和兼职的病理机制功能，该功能超出了其公认的细胞溶解活性。
