Bacterial cGAS-like enzymes synthesize diverse nucleotide signals

• Published in: Nature (London) Vol. 567; no. 7747; pp. 194 - 199
• Main Authors: Whiteley, Aaron T., Eaglesham, James B., de Oliveira Mann, Carina C., Morehouse, Benjamin R., Lowey, Brianna, Nieminen, Eric A., Danilchanka, Olga, King, David S., Lee, Amy S. Y., Mekalanos, John J., Kranzusch, Philip J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2019; Nature Publishing Group
• Subjects: 13; 13/106; 140/131; 38; 631/250/262/2106; 631/326/41/2531; 631/326/41/2533; 631/45/500; 631/45/535/1266; 64; 82; 82/58; 82/83; Alkaloids; Animals; Bacteria; Bacterial host response; Bacterial pathogenesis; Bacterial Proteins - metabolism; BASIC BIOLOGICAL SCIENCES; Biochemistry; Biological products; Cells (Biology); Crystal structure; Crystallography, X-Ray; Deoxyribonucleic acid; Dinucleoside Phosphates - biosynthesis; Dinucleoside Phosphates - metabolism; DNA; DNA polymerase; E coli; Enzymes; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Immune response; Infection; Mice; Microbial enzymes; Microbiota; Microbiota (Symbiotic organisms); multidisciplinary; Nucleotides; Nucleotides - biosynthesis; Nucleotides - chemistry; Nucleotides - metabolism; Nucleotidyltransferases - chemistry; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Operon - genetics; Pandemics; Pathogenic microorganisms; Pattern recognition; Pattern recognition receptors; Physiological aspects; Pyrimidine nucleotides; Pyrimidines; Receptors; RNA; Science; Science (multidisciplinary); Second messengers; Signaling; Symbiosis; Synthesis; Virulence; Virulence (Microbiology); X-ray crystallography; United States > US
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-0953-5

Cyclic dinucleotides (CDNs) have central roles in bacterial homeostasis and virulence by acting as nucleotide second messengers. Bacterial CDNs also elicit immune responses during infection when they are detected by pattern-recognition receptors in animal cells. Here we perform a systematic biochemical screen for bacterial signalling nucleotides and discover a large family of cGAS/DncV-like nucleotidyltransferases (CD-NTases) that use both purine and pyrimidine nucleotides to synthesize a diverse range of CDNs. A series of crystal structures establish CD-NTases as a structurally conserved family and reveal key contacts in the enzyme active-site lid that direct purine or pyrimidine selection. CD-NTase products are not restricted to CDNs and also include an unexpected class of cyclic trinucleotide compounds. Biochemical and cellular analyses of CD-NTase signalling nucleotides demonstrate that these cyclic di- and trinucleotides activate distinct host receptors and thus may modulate the interaction of both pathogens and commensal microbiota with their animal and plant hosts. A bacterial family of cGAS/DncV-like nucleotidyltransferases synthesizes a diverse range of cyclic dinucleotide and trinucleotide compounds that are likely to modulate the interaction of both pathogens and commensal microbiota with their animal and plant hosts.