Sensing of Bacterial Cyclic Dinucleotides by the Oxidoreductase RECON Promotes NF-κB Activation and Shapes a Proinflammatory Antibacterial State

Abstract

SUMMARY Bacterial and host cyclic dinucleotides (cdNs) mediate cytosolic immune responses through the STING signaling pathway, though evidence suggests alternative pathways exist. We used cdN-conjugated beads to biochemically isolate host receptors for bacterial cdNs, and identified the oxidoreductase RECON. High-affinity cdN binding inhibited RECON enzyme activity by simultaneously blocking the substrate and co-substrate sites, as revealed by structural analyses. During bacterial infection of macrophages, RECON antagonized STING activation by acting as a molecular sink for cdNs. Bacterial infection of hepatocytes, which do not express STING, revealed that RECON negatively regulates NF-κB activation. Loss of RECON activity, via genetic ablation or inhibition by cdNs, resulted in increased NF-κB activation and reduced bacterial survival, suggesting that cdN inhibition of RECON promotes a proinflammatory, antibacterial state that is distinct from the anti-viral state associated with STING activation. Thus, RECON functions as a cytosolic pattern recognition receptor specific for bacterial cdNs, shaping inflammatory gene activation via its effects on STING and NF-κB.

HORMA domain proteins and a Pch2-like ATPase regulate bacterial cGAS-like enzymes to mediate bacteriophage immunity

“…In mammals, cGAMP and linear oligoadenylate are important innate-immune signals, synthesized by cGAS (cyclic GMP-AMP synthase) and OAS (oligoadenylate synthase) family proteins in response to cytoplasmic DNA or double-stranded RNA (Chen et al, 2016;Hornung et al, 2014). Nucleotide-based second messengers also mediate cross-kingdom signaling, with mammalian innate immune receptors able to recognize and respond to a variety of bacterially-generated second messengers (Burdette et al, 2011;McFarland et al, 2017;.…”

Hemostatic, anti-inflammatory and antibacterial effects of Sanqixiantao dressing <i>in vivo</i> and <i>in vitro</i>

“…The present study revealed that sanqixiantao extracts alleviated the inflammation and significantly decreased the serum levels of pro-inflammatory cytokines such as TNF-α and IL-6 [24]. Bacterial infections usually result in the exacerbation of wounds and severe inflammatory reactions [25]. The results also demonstrated that sanqixiantao extract had significant antibacterial activities against six pathogenic bacteria that cause wound infection (E. coli, S. aureus, P. aeruginosa, S. epidermidis, C. perfringens and C. tetani).…”

cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity

“…The ER membrane adaptor ERAdP was recently identified as a direct sensor for c‐di‐AMP . Mouse oxidoreductase RECON has been classified as a sensor for some bacterial CDNs which modulate NF‐κB activation independently of STING through which they shape a proinflammatory antibacterial response . Here, we determined that the DNA sensor cGAS is involved in the engagement of endocytosed eCDNs, prior to STING activation.…”