Bacterial cGAS-like enzymes synthesize diverse nucleotide signals.

Nature
Aaron T WhiteleyPhilip J Kranzusch

Abstract

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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Methods Mentioned

BETA
NMR
X-ray
size-exclusion chromatography
Assay
transfection
affinity purification

Key Resources (RRID) Mentioned

AB_91531
AB_11204167
AB_2721181
AB_2687825

Software Mentioned

SOLVE
BLAST
RESOLVE
Geneious
MolProbity
PHENIX
MAFFT FFT - NS
GraphPad Prism
Prism
XDS

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