Plant intracellular nucleotide-binding leucine-rich repeat (NLR) receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain sense pathogen effectors to initiate immune signaling. TIR domains across different kingdoms have NADase activities and can produce phosphoribosyl adenosine monophosphate/diphosphate (pRib-AMP/ADP) or cyclic ADPR (cADPR) isomers. The lipase-like proteins EDS1 and PAD4 transduce immune signals from sensor TIR-NLRs to a helper NLR called ADR1, which executes immune function. We report the structure and function of an Arabidopsis EDS1-PAD4-ADR1 (EPA) heterotrimer in complex with pRib-AMP/ADP activated by plant or bacterial TIR signaling. 2'cADPR can be hydrolyzed into pRib-AMP and thus activate EPA signaling. Bacterial TIR domains producing 2'cADPR also activate EPA function. Our findings suggest that 2'cADPR may be the storage form of the unstable signaling molecule pRib-AMP.