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

Adelle P. McFarland, Shukun Luo, Fariha Ahmed-Qadri, Meghan Zuck, Elizabeth F. Thayer, Young Ah Goo, Kevin Hybiske, Liang Tong, Joshua J. Woodward*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Bacterial and host cyclic dinucleotides (cdNs) mediate cytosolic immune responses through the STING signaling pathway, although evidence suggests that alternative pathways exist. We used cdN-conjugated beads to biochemically isolate host receptors for bacterial cdNs, and we identified the oxidoreductase RECON. High-affinity cdN binding inhibited RECON enzyme activity by simultaneously blocking the substrate and cosubstrate 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, increased NF-κB activation and reduced bacterial survival, suggesting that cdN inhibition of RECON promotes a proinflammatory, antibacterial state that is distinct from the antiviral state associated with STING activation. Thus, RECON functions as a cytosolic sensor for bacterial cdNs, shaping inflammatory gene activation via its effects on STING and NF-κB.

Original languageEnglish (US)
Pages (from-to)433-445
Number of pages13
JournalImmunity
Volume46
Issue number3
DOIs
StatePublished - Mar 21 2017

Keywords

  • AKR1C13
  • Cyclic dinucleotides
  • Listeria monocytogenes
  • NF-κB
  • RECON
  • STING
  • aldo-keto reductase
  • cyclic di-AMP
  • pattern recognition receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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