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

• Published in: Nature immunology Vol. 15; no. 4; pp. 343 - 353
• Main Authors: Khare, Sonal, Ratsimandresy, Rojo A, de Almeida, Lúcia, Cuda, Carla M, Rellick, Stephanie L, Misharin, Alexander V, Wallin, Melissa C, Gangopadhyay, Anu, Forte, Eleonora, Gottwein, Eva, Perlman, Harris, Reed, John C, Greaves, David R, Dorfleutner, Andrea, Stehlik, Christian
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2014; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/21; 13/31; 13/51; 13/89; 13/95; 14/1; 14/35; 14/5; 14/63; 38/77; 38/90; 45/29; 631/250/256/2177; 64/110; 82/80; 82/83; 96/106; Adaptor proteins; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Animals; Autoimmune diseases; Biomedicine; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase 1 - metabolism; Caspase-1; Deoxyribonucleic acid; DNA; DNA virus infections; DNA Virus Infections - immunology; DNA viruses; DNA Viruses - immunology; DNA-Binding Proteins; HEK293 Cells; Homeostasis; Humans; Immune response; Immune system; Immunity - genetics; Immunology; Infectious Diseases; Inflammasomes; Inflammasomes - metabolism; Innate immunity; Interferon Type I - genetics; Interferon Type I - immunology; Interferon-gamma - genetics; Interferon-gamma - immunology; Macrophages; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Monocytes; mTOR Associated Protein, LST8 Homolog; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nuclear Proteins - metabolism; Physiological aspects; Physiological research; Protein Binding - genetics; Protein Structure, Tertiary - genetics; Proteins; Pyrin protein; Sequence Alignment; Transgenes - genetics; Viral Proteins - genetics
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2829

Much is known about the activation of inflammasomes, but less is known about their negative regulation. Stehlik and colleagues demonstrate that the pyrin domain–only protein POP3 negatively regulates inflammasomes involved in sensing DNA.
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.