Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling

Science. 2022 Sep 30;377(6614):eadc8969. doi: 10.1126/science.adc8969. Epub 2022 Sep 30.


Cyclic adenosine diphosphate (ADP)-ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD+) hydrolysis. We show that v-cADPR (2'cADPR) and v2-cADPR (3'cADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2'cADPR-producing TIR domains reveal conformational changes that lead to an active assembly that resembles those of Toll-like receptor adaptor TIR domains. Mutagenesis reveals a conserved tryptophan that is essential for cyclization. We show that 3'cADPR is an activator of ThsA effector proteins from the bacterial antiphage defense system termed Thoeris and a suppressor of plant immunity when produced by the effector HopAM1. Collectively, our results reveal the molecular basis of cADPR isomer production and establish 3'cADPR in bacteria as an antiviral and plant immunity-suppressing signaling molecule.

MeSH terms

  • ADP-ribosyl Cyclase* / chemistry
  • ADP-ribosyl Cyclase* / genetics
  • ADP-ribosyl Cyclase* / metabolism
  • Adaptor Proteins, Vesicular Transport* / chemistry
  • Adaptor Proteins, Vesicular Transport* / genetics
  • Adaptor Proteins, Vesicular Transport* / metabolism
  • Bacteria* / immunology
  • Bacteria* / virology
  • Bacterial Proteins* / chemistry
  • Bacterial Proteins* / genetics
  • Bacterial Proteins* / metabolism
  • Cyclic ADP-Ribose* / biosynthesis
  • Cyclic ADP-Ribose* / chemistry
  • Isomerism
  • NAD / metabolism
  • Plant Immunity*
  • Protein Domains
  • Receptors, Interleukin-1 / chemistry
  • Signal Transduction
  • Toll-Like Receptors* / chemistry
  • Toll-Like Receptors* / genetics
  • Toll-Like Receptors* / metabolism
  • Tryptophan / chemistry
  • Tryptophan / genetics


  • Adaptor Proteins, Vesicular Transport
  • Bacterial Proteins
  • Receptors, Interleukin-1
  • Toll-Like Receptors
  • NAD
  • Cyclic ADP-Ribose
  • Tryptophan
  • ADP-ribosyl Cyclase