PMID:27911947

Citation	Ratner, D, Orning, MP, Proulx, MK, Wang, D, Gavrilin, MA, Wewers, MD, Alnemri, ES, Johnson, PF, Lee, B, Mecsas, J, Kayagaki, N, Goguen, JD and Lien, E (2016) The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS Pathog. 12:e1006035
Abstract	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.
Links	PubMed PMC5135138 Online version:10.1371/journal.ppat.1006035
Keywords	Animals; Bacterial Outer Membrane Proteins/immunology; Disease Models, Animal; Inflammasomes/immunology; Mice; Mice, Knockout; Plague/immunology; Pyrin/immunology; Yersinia pestis/immunology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
YERPE:YOPM		GO:1990001: inhibition of cysteine-type endopeptidase activity involved in apoptotic process	ECO:0000279: qualitative western immunoblotting evidence used in manual assertion		P		Figure 2D shows Western Blot data showing decreased pro-Caspase-1 and IL-1B, the inactive form of Caspase-1 that plays a role in Pyrin Inflammasome activation and the inactive form of IL-1B that is activated by Caspase-1, respectively, in the YopM mutants. This is indicative of more activation of Caspase-1 and IL-1B in the absence of YopM, which implies increased Pyrin Inflammasome activation. The figure also shows increased IL-1B in the YopM mutant, which inversely corresponds with the IL-1B protein expression data. Yersinia pests	complete CACAO 13587
YERPE:O68704		GO:1900226: negative regulation of NLRP3 inflammasome complex assembly	ECO:0005581: enzyme-linked immunoabsorbent assay evidence used in manual assertion		P		Figure 3E,G YopK mutants showed a sharp increase in IL-1B production in 3E. 3G shows the independence of this effect on Pyrin, but its dependence on NLRP3/NLRC4 pathway. Yersinia pestis	complete CACAO 13599

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