期刊
NATURE
卷 567, 期 7747, 页码 194-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-0953-5
关键词
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资金
- Claudia Adams Barr Program for Innovative Cancer Research
- Richard and Susan Smith Family Foundation
- Charles H. Hood Foundation
- Cancer Research Institute CLIP Grant
- NIH/NIAID [R01AI018045, R01AI026289]
- Searle Scholars Program
- Sloan Research Fellowship
- NIH T32 Cancer Immunology training grant [5T32CA207021-02]
- Jane Coffin Childs Memorial Fund for Medical Research
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.
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