title: 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.
authors.affiliation: UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Ratner
authors.affiliation: UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America.|Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: M Pontus A
authors.initials: MP
authors.lastname: Orning
authors.affiliation: UMass Medical School, Department of Microbiology and Physiological Systems, Worcester, Massachusetts, United States of America.
authors.forename: Megan K
authors.identifier: http://orcid.org/0000-0002-9524-8302
authors.initials: MK
authors.lastname: Proulx
authors.affiliation: UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America.|Department of Medicine, School of Medicine, Duke University, Durham, North Carolina, United States of America.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wang
authors.affiliation: Davis Heart and Lung Research Institute, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Gavrilin
authors.affiliation: Davis Heart and Lung Research Institute, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mark D
authors.identifier: http://orcid.org/0000-0002-7079-5633
authors.initials: MD
authors.lastname: Wewers
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
authors.affiliation: Department of Physiological Chemistry, Genentech, Inc., South San Francisco, California, United States of America.
authors.forename: Bettina
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Joan
authors.initials: J
authors.lastname: Mecsas
authors.affiliation: Department of Physiological Chemistry, Genentech, Inc., South San Francisco, California, United States of America.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.affiliation: UMass Medical School, Department of Microbiology and Physiological Systems, Worcester, Massachusetts, United States of America.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Goguen
authors.affiliation: UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America.|Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010930:Plague / Q000276:immunology*; D000071198:Pyrin / Q000276:immunology*; D015010:Yersinia pestis / Q000276:immunology
chemical_list: D001425:Bacterial Outer Membrane Proteins; D058847:Inflammasomes; D000071198:Pyrin; C060772:yopM protein, Yersinia