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.

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Published Version (Please cite this version)

10.1371/journal.ppat.1006035

Publication Info

Ratner, Dmitry, M Pontus A Orning, Megan K Proulx, Donghai Wang, Mikhail A Gavrilin, Mark D Wewers, Emad S Alnemri, Peter F Johnson, et al. (2016). The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS pathogens, 12(12). p. e1006035. 10.1371/journal.ppat.1006035 Retrieved from https://hdl.handle.net/10161/18595.

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Wang

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 responses. Studies of these hereditary human disorders have provided invaluable insight into basic cellular and molecular mechanisms of the innate immune responses and have contributed significantly to the development of targeted therapies for common human inflammatory diseases such as arthritis. My long term goal is to understand the pathophysiological mechanisms of autoinflammatory diseases and to apply knowledge from such studies to develop novel treatment of inflammatory human diseases. Our recent studies of one of such diseases, namely mevalonate kinase deficiency, has allowed us to unravel the unexpected connection between the cholesterol-biosynthesis mevalonate pathway and toll like receptor (TLR)-mediated phosphatidyl inosital 3(PI3)-kinase signaling. These exciting new discoveries will greatly advance our knowledge of innate immune signaling and may provide clues for new interventions of a variety of human diseases.


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