Open AccessBacterial cGAS-like enzymes synthesize diverse nucleotide signals
Author(s) -
Aaron T. Whiteley,
J.B. Eaglesham,
Carina C. de Oliveira Mann,
B.R. Morehouse,
B. Lowey,
E.A. Nieminen,
Olga Danilchanka,
David S. King,
A.S.Y. Lee,
John J. Mekalanos,
Philip J. Kranzusch
Publication year - 2019
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-019-0953-5
Subject(s) - purine , nucleotide , biology , second messenger system , enzyme , virulence , cyclic nucleotide , biochemistry , receptor , signal transduction , microbiology and biotechnology , gene
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.