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      The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

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          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.

          Author Summary

          Many pathogenic Gram-negative bacteria express type III secretion systems (T3SS) that translocate bacterial proteins into host cells with the potential of altering normal cell processes. Yersinia pestis, the causative agent of plague, harbors a T3SS which is particularly effective in suppressing innate immunity and release of pro-inflammatory cytokines IL-1β and IL-18, potent triggers of anti-bacterial responses. These cytokines are produced via processing by active caspase-1 in inflammasome complexes. Pyrin is an inflammasome component that recognizes alterations in certain host cell signals. Here we show that the T3SS effector protein YopM inhibits effector YopE-mediated Pyrin-induced caspase-1 activation, IL-1β, IL-18 and cell death triggered by Y. pestis. We also found that blocking the Pyrin pathway is important for disease development in a mouse model of bubonic plague. Thus, YopM is a microbial molecule blocking Pyrin inflammasomes.

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          Most cited references32

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          Pyrin Inflammasome Activation and RhoA Signaling in the Autoinflammatory Diseases FMF and HIDS

          Mutations of pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases, familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutated or in response to bacterial modification of the GTPase RhoA. Here we show that RhoA activates the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin binds 14-3-3 proteins, which block the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin is substantially decreased, and the constitutive IL-1β release from FMF or HIDS patients’ peripheral blood mononuclear cells is attenuated by activating PKN1 and PKN2. Defects in prenylation, seen in HIDS, lead to RhoA inactivation and consequent pyrin inflammasome activation. These data indicate a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders.
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            Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis.

            A type III secretion system (TTSS) is encoded on a virulence plasmid that is common to three pathogenic Yersinia species: Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis. Pathogenic Yersinia species require this TTSS to survive and replicate within lymphoid tissues of their animal or human hosts. A set of pathogenicity factors, including those known as Yersinia outer proteins (Yops), is exported by this system upon bacterial infection of host cells. Two translocator Yops (YopB and YopD) insert into the host plasma membrane and function to transport six effector Yops (YopO, YopH, YopM, YopT, YopJ, and YopE) into the cytosol of the host cell. Effector Yops function to counteract multiple signaling responses in the infected host cell. The signaling responses counteracted by Yops are initiated by phagocytic receptors, Toll-like receptors, translocator Yops, and additional mechanisms. Innate and adaptive immune responses are thwarted as a consequence of Yop activities. A biochemical function for each effector Yop has been established, and the importance of these proteins for the pathogenesis process is being elucidated. This review focuses on the biochemical functions of Yops, the signaling pathways they modulate, and the role of these proteins in Yersinia virulence.
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              The NLRP12 inflammasome recognizes Yersinia pestis.

              Yersinia pestis, the causative agent of plague, is able to suppress production of inflammatory cytokines IL-18 and IL-1β, which are generated through caspase-1-activating nucleotide-binding domain and leucine-rich repeat (NLR)-containing inflammasomes. Here, we sought to elucidate the role of NLRs and IL-18 during plague. Lack of IL-18 signaling led to increased susceptibility to Y. pestis, producing tetra-acylated lipid A, and an attenuated strain producing a Y. pseudotuberculosis-like hexa-acylated lipid A. We found that the NLRP12 inflammasome was an important regulator controlling IL-18 and IL-1β production after Y. pestis infection, and NLRP12-deficient mice were more susceptible to bacterial challenge. NLRP12 also directed interferon-γ production via induction of IL-18, but had minimal effect on signaling to the transcription factor NF-κB. These studies reveal a role for NLRP12 in host resistance against pathogens. Minimizing NLRP12 inflammasome activation may have been a central factor in evolution of the high virulence of Y. pestis. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                2 December 2016
                December 2016
                : 12
                : 12
                : e1006035
                Affiliations
                [1 ]UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America
                [2 ]Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
                [3 ]UMass Medical School, Department of Microbiology and Physiological Systems, Worcester, Massachusetts, United States of America
                [4 ]Department of Medicine, School of Medicine, Duke University, Durham, North Carolina, United States of America
                [5 ]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
                [6 ]Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
                [7 ]Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America
                [8 ]Department of Physiological Chemistry, Genentech, Inc., South San Francisco, California, United States of America
                [9 ]Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
                University of Pennsylvania, UNITED STATES
                Author notes

                BL and NK are employees of Genentech, Inc.

                • Conceptualization: EL.

                • Funding acquisition: DR DW MAG MDW ESA PFJ JM EL.

                • Investigation: DR MPAO NK EL.

                • Resources: DR MKP DW MAG MDW ESA PFJ BL JM NK JDG.

                • Supervision: EL.

                • Writing – original draft: DR EL.

                • Writing – review & editing: DR MPAO MKP DW MAG MDW ESA PFJ BL JM NK JDG EL.

                Author information
                http://orcid.org/0000-0002-9524-8302
                http://orcid.org/0000-0002-7079-5633
                Article
                PPATHOGENS-D-16-01946
                10.1371/journal.ppat.1006035
                5135138
                27911947
                30527e89-4704-45f3-a3ac-2961124ac216

                This 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.

                History
                : 23 August 2016
                : 31 October 2016
                Page count
                Figures: 6, Tables: 0, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI07538
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI095213
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: HL076278
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000069, National Institute of Arthritis and Musculoskeletal and Skin Diseases;
                Award ID: AR055398
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI113166
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI110695
                Award Recipient :
                Funded by: Kreftforeningen (NO)
                Award Recipient :
                Funded by: Norges Forskningsråd (NO)
                Award ID: 223255/F50
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: U19 AI057319
                Award Recipient :
                The work was supported by National Institutes of Health Grants AI07538 and U19 AI057319 (to EL), AI095213 (to DR), HL076278 (to MAG and MDW), AR055398 (to ESA), AI113166 (to JM), AI110695 (to DW), the Norwegian Cancer Society, and Research Council of Norway Center of Excellence Funding Scheme Project 223255/F50 (to EL). The research of PFJ was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. URLs: https://www.nih.gov/, https://kreftforeningen.no/, http://www.forskningsradet.no/en/Home_page/1177315753906, http://www.cancer.gov/
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