LPS targets host guanylate‐binding proteins to the bacterial outer membrane for non‐canonical inflammasome activation. (19th February 2018)

• Record Type: Journal Article
• Authors: Santos, José Carlos; Dick, Mathias S; Lagrange, Brice; Degrandi, Daniel; Pfeffer, Klaus; Yamamoto, Masahiro; Meunier, Etienne; Pelczar, Pawel; Henry, Thomas; Broz, Petr
• Is Part Of: EMBO journal. Volume 37:Number 6(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-02-19
• Subjects: caspase‐11 -- guanylate‐binding proteins (GBPs) -- inflammasome -- LPS -- outer membrane vesicles; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201798089
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Cytosolic immune detection of LPS in mouse macrophages is promoted by guanylate‐binding proteins (GBPs) that associate with LPS‐containing membranes and hereby promote the interaction of LPS to caspase‐11, which is constitutes the non‐canonical inflammasome. Bacterial OMVs induce production of type‐I interferons through TLR4‐TRIF signaling, triggering expression of cytosolic GBPs. Isoprenylated GBPs are recruited to cytosolic OMVs, which drives activation of the caspase‐11 non‐canonical inflammasome. LPS is the key factor of the outer bacterial membrane that promotes GBP recruitment and GBP‐dependent inflammasome activation. GBPs also facilitate caspase‐11 binding to transfected cytosolic bacterial LPS. In vivo, GBPs promote endotoxic shock induced by OMV‐derived LPS. Abstract : Immunogenicity of bacterial outer membrane vesicles is linked to lipopolysaccharide delivery and TLR4‐TRIF signaling in host macrophages.