Editors' ChoiceHost-Pathogen Interactions

Diverse bacterial nucleotide signals

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Sci. Signal.  19 Mar 2019:
Vol. 12, Issue 573, eaax3389
DOI: 10.1126/scisignal.aax3389

Bacterial enzymes synthesize a range of different cyclic nucleotides that activate distinct host cell receptors.

In bacteria, cyclic dinucleotides (CDNs), which were thought to be generated from only purine nucleotides, have important roles in bacterial homeostasis and virulence, and they also trigger immune responses during infection through their detection by pattern recognition receptors. Whiteley et al. found a dinucleotide cyclase in Escherichia coli, CdnE, that synthesized cyclic UMP–AMP (cUMP-AMP), a hybrid CDN containing both a purine and a pyrimidine. CdnE and its homolog from Vibrio cholerae, DncV, are structural homologs of cGAS, the mammalian enzyme that synthesizes cGAMP, a CDN that binds to the sensor STING to induce innate immune responses. The authors identified a shared amino acid sequence that formed the active site and then classified these enzymes as cGAS/DncV-like nucleotidyltransferases (CD-NTases). Mutation of Asn166 of CdnE resulted in the variant enzyme producing c-di-AMP instead of cUMP-AMP, indicating an important role for this site in determining product specificity. Reporter assays in HEK 293T cells showed that whereas STING failed to detect cUMP-AMP, this hybrid dinucleotide was detected by the CDN sensor RECON (reductase controlling NF-κB). Through a combination of bioinformatics analysis and biochemical screening of 66 different CD-NTases, the authors identified seven purine, pyrimidine, and purine-pyrimidine hybrid CDNs. Further analyses of CD-NTase products identified cyclic AMP–AMP–GMP (cAAG), a previously unknown cyclic trinucleotide, which was undetected by STING, but was detected by RECON. Solving the structure of cAAG-bound RECON showed that the conserved residue Glu28 in the binding site made contact with the third guanine base of cAAG, suggesting that it may have evolved to detect this species of bacterial CDN. Together, these findings highlight the diverse range of nucleotide signaling molecules produced by bacteria, some of which trigger STING-independent innate immune responses and may modulate host-pathogen interactions.

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