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The PYRIN domain–only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses

Nature Immunology volume 15, pages 343353 (2014) | Download Citation

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Abstract

The innate immune system responds to infection and tissue damage by activating cytosolic sensory complexes called 'inflammasomes'. Cytosolic DNA is sensed by AIM2-like receptors (ALRs) during bacterial and viral infections and in autoimmune diseases. Subsequently, recruitment of the inflammasome adaptor ASC links ALRs to the activation of caspase-1. A controlled immune response is crucial for maintaining homeostasis, but the regulation of ALR inflammasomes is poorly understood. Here we identified the PYRIN domain (PYD)-only protein POP3, which competes with ASC for recruitment to ALRs, as an inhibitor of DNA virus–induced activation of ALR inflammasomes in vivo. Data obtained with a mouse model with macrophage-specific POP3 expression emphasize the importance of the regulation of ALR inflammasomes in monocytes and macrophages.

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Acknowledgements

We thank B.C. Schaefer (Uniformed Services University of the Health Sciences) for the promoter of the gene encoding ubiquitin C; J. DeGregori (University of Colorado Health Sciences Center) for the plasmid pLXS-hCARΔcyt; D. Trono (École Polytechnique Fédérale de Lausanne) for plasmids pMD2.G and psPAX2; K.A. Fitzgerald (University of Massachusetts) for Aim2−/− mice; the Northwestern University Transgenic and Targeted Mutagenesis Laboratory for assistance in generating transgenic mice; and A.D. Radian for the isolation of human macrophages. Supported by the US National Institutes of Health (GM071723, HL097183, AI092490, AI082406, AI099009 and AR064349 to C.S.; AR057532 to A.D., AR050250, AR054796, AI092490 and HL108795 to H.P.; AR064313 to C.M.C.; and T32AR007611 to L.d.A.), the National Cancer Institute (CA060553), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR057216), the American Heart Association (12GRNT12080035 to C.S.), the Arthritis Foundation (AF161715 to S.K.), the American Heart Association (11POST585000 to L.d.A.) and the Solovy/Arthritis Research Society (H.P.).

Author information

Author notes

    • Stephanie L Rellick

    Present address: Center for Neuroscience, Health Sciences Center, West Virginia University, Morgantown, West Virginia, USA.

Affiliations

  1. Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Sonal Khare
    • , Rojo A Ratsimandresy
    • , Lúcia de Almeida
    • , Carla M Cuda
    • , Alexander V Misharin
    • , Melissa C Wallin
    • , Anu Gangopadhyay
    • , Harris Perlman
    • , Andrea Dorfleutner
    •  & Christian Stehlik
  2. Program in Cancer Cell Biology, Health Sciences Center, West Virginia University, Morgantown, West Virginia, USA.

    • Stephanie L Rellick
  3. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Eleonora Forte
    •  & Eva Gottwein
  4. Apoptosis and Cell Death Research Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.

    • John C Reed
  5. Pharma Research and Early Development, F. Hoffmann–La Roche, Basel, Switzerland.

    • John C Reed
  6. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

    • David R Greaves
  7. Robert H. Lurie Comprehensive Cancer Center, Interdepartmental Immunobiology Center and Skin Disease Research Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Christian Stehlik

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Contributions

A.D. and C.S. designed the research; S.K., R.A.R., L.d.A., C.M.C., S.L.R., A.V.M., M.C.W. and A.G. did experiments; E.F., E.G., H.P., J.C.R. and D.R.G. provided reagents, expertise and advice; S.K., R.A.R., L.d.A., C.M.C., A.V.M., H.P., A.D. and C.S. analyzed results; S.K., A.D. and C.S. wrote the paper; and A.D. and C.S. conceived of the study, designed the experiments and provided overall direction.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Andrea Dorfleutner or Christian Stehlik.

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DOI

https://doi.org/10.1038/ni.2829

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