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The discovery of the enzymatic activity of the toll/interleukin-1 receptor (TIR) domain protein SARM1 five years ago preceded a flood of discoveries regarding the nucleotide substrates and products of TIR domains in plants, animals, bacteria, and archaea. These discoveries into the activity of TIR domains coincide with major advances in understanding the structure and mechanisms of NOD-like receptors and the mutual dependence of pattern recognition receptor– and effector-triggered immunity (PTI and ETI, respectively) in plants. It is quickly becoming clear that TIR domains and TIR-produced nucleotides are ancestral signaling molecules that modulate immunity and that their activity is closely associated with Ca2+signaling. TIR domain research now bridges the separate disciplines of molecular plant- and animal-microbe interactions, neurology, and prokaryotic immunity. A cohesive framework for understanding the role of enzymatic TIR domains in diverse organisms will help unite the research of these disparate fields. Here, we review known products of TIR domains in plants, animals, bacteria, and archaea and use context gained from animal and prokaryotic TIR domain systems to present a model for TIR domains, nucleotides, and Ca2+at the intersection of PTI and ETI in plant immunity.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .

The Pseudomonas syringae DC3000 type III effector HopAM1 suppresses plant immunity and contains a Toll/interleukin-1 receptor (TIR) domain homologous to immunity-related TIR domains of plant nucleotide-binding leucine-rich repeat receptors that hydrolyze nicotinamide adenine dinucleotide (NAD+ ) and activate immunity. In vitro and in vivo assays were conducted to determine if HopAM1 hydrolyzes NAD+ and if the activity is essential for HopAM1's suppression of plant immunity and contribution to virulence. HPLC and LC-MS were utilized to analyze metabolites produced from NAD+ by HopAM1 in vitro and in both yeast and plants. Agrobacterium-mediated transient expression and in planta inoculation assays were performed to determine HopAM1's intrinsic enzymatic activity and virulence contribution. HopAM1 is catalytically active and hydrolyzes NAD+ to produce nicotinamide and a novel cADPR variant (v2-cADPR). Expression of HopAM1 triggers cell death in yeast and plants dependent on the putative catalytic residue glutamic acid 191 (E191) within the TIR domain. Furthermore, HopAM1's E191 residue is required to suppress both pattern-triggered immunity and effector-triggered immunity and promote P. syringae virulence. HopAM1 manipulates endogenous NAD+ to produce v2-cADPR and promote pathogenesis. This work suggests that HopAM1's TIR domain possesses different catalytic specificity than other TIR domain-containing NAD+ hydrolases and that pathogens exploit this activity to sabotage NAD+ metabolism for immune suppression and virulence.