The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

Type iii secretion systems (t3ss) are central virulence factors for many pathogenic gram-negative bacteria,and secreted t3ss effectors can block key aspects of host cell signaling. to counter this,innate immune responses can also sense some t3ss components to initiate anti-bacterial mechanisms. the yersinia pestis t3ss is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines il-1β and il-18,which are typically processed into their mature forms by active caspase-1 following inflammasome formation. some effectors,like y. pestis yopm,may block inflammasome activation. here we show that yopm prevents y. pestis induced activation of the pyrin inflammasome induced by the rhoa-inhibiting effector yope,which is a gtpase activating protein. yopm blocks yope-induced pyrin-mediated caspase-1 dependent il-1β/il-18 production and cell death. we also detected yopm in a complex with pyrin and kinases rsk1 and pkn1,putative negative regulators of pyrin. in contrast to wild-type mice,pyrin deficient mice were also highly susceptible to an attenuated y. pestis strain lacking yopm,emphasizing the importance of inhibition of pyrin in vivo. a complex interplay between the y. pestis t3ss and il-1β/il-18 production is evident,involving at least four inflammasome pathways. the secreted effector yopj triggers caspase-8- dependent il-1β activation,even when yopm is present. additionally,the presence of the t3ss needle/translocon activates nlrp3 and nlrc4-dependent il-1β 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-1β/il-18 release suggests that these effects are essential for maximal control of innate immunity during plague. © 2016 public library of science. all rights reserved.