A nucleoside signal generated by a fungal endophyte regulates host cell death and promotes root colonization

The intracellular colonization of plant roots by the beneficial fungal endophyte Serendipita indica follows a biphasic strategy, including a host cell death phase that enables successful colonization of Arabidopsis thaliana roots. How host cell death is initiated and controlled is largely unknown. Here, we show that two fungal enzymes, the ecto-5'-nucleotidase SiE5NT and the nuclease SiNucA, act synergistically in the apoplast at the onset of cell death to produce deoxyadenosine (dAdo). The uptake of extracellular dAdo but not the structurally related adenosine activates cell death via the equilibrative nucleoside transporter ENT3. We identified a previously uncharacterized Toll-like interleukin 1 receptor (TIR)-nucleotide-binding leucine-rich repeat receptor (NLR) protein, ISI (induced by S. indica), as an intracellular factor that affects host cell death, fungal colonization, and growth promotion. Our data show that the combined activity of two fungal apoplastic enzymes promotes the production of a metabolite that engages TIR-NLR-modulated pathways to induce plant cell death, providing a link to immunometabolism in plants.