The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation.
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.
Type
Journal articleSubject
AnimalsMice, Knockout
Mice
Yersinia pestis
Plague
Disease Models, Animal
Bacterial Outer Membrane Proteins
Inflammasomes
Pyrin
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https://hdl.handle.net/10161/18595Published Version (Please cite this version)
10.1371/journal.ppat.1006035Publication Info
Ratner, Dmitry; Orning, M Pontus A; Proulx, Megan K; Wang, Donghai; Gavrilin, Mikhail
A; Wewers, Mark D; ... Lien, Egil (2016). The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS pathogens, 12(12). pp. e1006035. 10.1371/journal.ppat.1006035. Retrieved from https://hdl.handle.net/10161/18595.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Donghai Wang
Assistant Professor in Medicine
Inflammation underlies a variety of human diseases such as obesity, diabetes, cardiovascular
diseases, neurodegenerative diseases, arthritis and cancer. Together, these diseases
constitute a major challenge to the well being of modern human society. Understanding
the fundamental mechanisms of inflammation may provide rationales for designing novel
interventions to treat these maladies. Autoinflammatory diseases are an emerging family
of illness, characterized by dysregulation of innate immune re

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