Plant pathogens cleave 2′cADPR to suppress TIR immune signaling

Small molecules produced by TIR (Toll-interleukin-1 receptor) domains are essential for plant immune signaling. A central TIR-derived signal is 2'cADPR, a cyclic ADP-ribose (ADPR) molecule that is generated by plant TIR-domain proteins upon sensing pathogen infection. Here we show that XopQ, a virulence protein widespread in plant pathogenic bacteria, cleaves 2'cADPR and converts it into an inactive, linear ADPR molecule. Steady-state kinetic analyses revealed that XopQ is a highly efficient enzyme that hydrolyzes 2'cADPR with near diffusion-limited catalytic efficiency, while displaying high specificity and no detectable activity toward closely related molecules such as 3'cADPR. We show that XopQ eliminates 2'cADPR in planta and prevents accumulation of pRib-AMP, a derivative of 2'cADPR that activates the downstream immune complex EDS1-PAD4. Our data demonstrate that XopQ inhibits PAD4-dependent plant immunity and can promote pathogen virulence even when the pathogen carries an avirulence effector that triggers TIR-mediated immune signaling. Finally, we show that XopQ can also inhibit type VI Thoeris, a bacterial anti-phage defense system that relies on 2'cADPR signaling, possibly explaining why XopQ and type VI Thoeris are not observed co-occurring in bacterial genomes. Our findings uncover a widespread and conserved strategy used by plant pathogens to directly target host TIR signaling.