引用

III型分泌系统(T3SS)是许多致病性革兰氏阴性细菌的核心毒力因素，分泌的T3SS效应物可以阻断宿主细胞信号转导的关键方面。为了对抗这种情况，先天免疫反应也可以感知一些T3SS成分来启动抗菌机制。鼠疫耶尔森氏菌T3SS在控制促炎细胞因子IL-1和IL-18的产生方面特别有效和复杂，它们通常在炎性小体形成后由活性caspase-1加工成成熟形式。一些效应物，如鼠疫菌YopM，可能会阻止炎症小体的激活。在这里，我们发现YopM可以阻止鼠疫菌诱导的Pyrin炎症小体的激活，Pyrin炎症小体是由rhoa抑制效应物YopE诱导的，YopE是一种GTPase激活蛋白。YopM阻断yope诱导pyrin介导的依赖于caspase-1的IL-1/IL-18的产生和细胞死亡。我们还在Pyrin和激酶RSK1和PKN1的复合物中检测到YopM, RSK1和PKN1被认为是Pyrin的负调控因子。与野生型小鼠相比，Pyrin缺陷小鼠对缺乏YopM的减毒鼠疫菌菌株也高度敏感，这强调了体内抑制Pyrin的重要性。鼠疫菌T3SS和IL-1/IL-18产生之间的复杂相互作用是明显的，至少涉及四个炎症小体途径。分泌效应因子YopJ触发依赖于caspase-8的IL-1激活，即使YopM存在。 Additionally, the presence of the T3SS needle/translocon activates NLRP3 and NLRC4-dependent IL-1 generation, which is blocked by YopK, but not by YopM. Taken together, the data suggest YopM specificity for obstructing the Pyrin pathway, as the effector does not appear to block Y. pestis-induced NLRP3, NLRC4 or caspase-8 dependent caspase-1 processing. Thus, we identify Y. pestis YopM as a microbial inhibitor of the Pyrin inflammasome. The fact that so many of the Y. pestis T3SS components are participating in regulation of IL-1/IL-18 release suggests that these effects are essential for maximal control of innate immunity during plague.