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dc.contributor.authorRatner, Dmitry
dc.contributor.authorØrning, Mathias Pontus
dc.contributor.authorProulx, MK
dc.contributor.authorWang, Donghai
dc.contributor.authorGavrilin, Mikhail
dc.contributor.authorWewers, Mark
dc.contributor.authorAlnemri, Emad
dc.contributor.authorJohnson, Peter
dc.contributor.authorLee, Bettina
dc.contributor.authorMecsas, Joan
dc.contributor.authorKayagaki, Nobuhiko
dc.contributor.authorGoguen, JD
dc.contributor.authorLien, Egil
dc.date.accessioned2018-01-03T07:57:02Z
dc.date.available2018-01-03T07:57:02Z
dc.date.created2017-01-09T19:09:22Z
dc.date.issued2016
dc.identifier.issn1553-7366
dc.identifier.urihttp://hdl.handle.net/11250/2474183
dc.description.abstractType 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.nb_NO
dc.language.isoengnb_NO
dc.publisherPublic Library of Sciencenb_NO
dc.titleThe Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activationnb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.description.versionpublishedVersionnb_NO
dc.source.volume12nb_NO
dc.source.journalPLoS Pathogensnb_NO
dc.source.issue12nb_NO
dc.identifier.doi10.1371/journal.ppat.1006035
dc.identifier.cristin1423771
dc.relation.projectNorges forskningsråd: 223255nb_NO
dc.description.localcodeThis is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.nb_NO
cristin.unitcode194,65,15,0
cristin.unitnameInstitutt for klinisk og molekylær medisin
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode2


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