LPS targets host guanylate‐binding proteins to the bacterial outer membrane for non‐canonical inflammasome activation |
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Authors: | José Carlos Santos Mathias S Dick Brice Lagrange Daniel Degrandi Klaus Pfeffer Masahiro Yamamoto Etienne Meunier Pawel Pelczar Thomas Henry Petr Broz |
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Institution: | 1. Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland;2. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;3. Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR 5308, Université Claude Bernard Lyon‐1, Ecole Normale Supérieure, Lyon, France;4. Institute of Medical Microbiology and Hospital Hygiene, Heinrich‐Heine‐University Düsseldorf, Düsseldorf, Germany;5. Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;6. Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, Toulouse Cedex 04, France;7. Center for Transgenic Models, University of Basel, Basel, Switzerland |
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Abstract: | Pathogenic and commensal Gram‐negative bacteria produce and release outer membrane vesicles (OMVs), which present several surface antigens and play an important role for bacterial pathogenesis. OMVs also modulate the host immune system, which makes them attractive as vaccine candidates. At the cellular level, OMVs are internalized by macrophages and deliver lipopolysaccharide (LPS) into the host cytosol, thus activating the caspase‐11 non‐canonical inflammasome. Here, we show that OMV‐induced inflammasome activation requires TLR4‐TRIF signaling, the production of type I interferons, and the action of guanylate‐binding proteins (GBPs), both in macrophages and in vivo. Mechanistically, we find that isoprenylated GBPs associate with the surface of OMVs or with transfected LPS, indicating that the key factor that determines GBP recruitment to the Gram‐negative bacterial outer membranes is LPS itself. Our findings provide new insights into the mechanism by which GBPs target foreign surfaces and reveal a novel function for GBPs in controlling the intracellular detection of LPS derived from extracellular bacteria in the form of OMVs, thus extending their function as a hub between cell‐autonomous immunity and innate immunity. |
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Keywords: | caspase‐11 guanylate‐binding proteins (GBPs) inflammasome
LPS
outer membrane vesicles |
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