Sensing of Bacterial Cyclic Dinucleotides by the Oxidoreductase RECON Promotes NF-κB Activation and Shapes a Proinflammatory Antibacterial State.
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.
Department of Microbiology, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
Adelle P
AP
McFarland
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Shukun
S
Luo
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Fariha
F
Ahmed-Qadri
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Program in Infectious Diseases, School of Public Health, University of California at Berkeley, Berkeley, CA 94720, USA.
Meghan
M
Zuck
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Elizabeth F
EF
Thayer
Proteomics Center of Excellence, Northwestern University, Chicago, IL 60611, USA.
Young Ah
YA
Goo
Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Kevin
K
Hybiske
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Liang
L
Tong
Department of Microbiology, University of Washington, Seattle, WA 98195, USA. Electronic address: jjwoodwa@uw.edu.
Joshua J
JJ
Woodward
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D004960:Estradiol Dehydrogenases / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D001426:Bacterial Proteins; D016328:NF-kappa B; C524623:AKR1C13 protein, mouse; D004960:Estradiol Dehydrogenases
AKR1C13; Cyclic dinucleotides; Listeria monocytogenes; NF-κB; RECON; STING; aldo-keto reductase; cyclic di-AMP; pattern recognition receptor