Transcriptional activation of plant immunity by salicylic acid.

The plant defence hormone salicylic acid (SA) triggers systemic acquired resistance by signalling through its receptor, NON-EXPRESSOR OF PATHOGENESIS-RELATED GENE 1 (NPR1), leading to widespread transcriptional reprogramming1,2. However, the molecular mechanism by which NPR1 senses SA and activates transcription remains unresolved. Here we show that SA stabilizes the SA-binding domain (SBD) of NPR1 and allosterically promotes its interaction with MED15A, a subunit of the Mediator complex. Leveraging the NPR1 proxiome and AlphaFold structural predictions, we identify a direct interaction between NPR1 and the kinase-inducible domain interacting (KIX) domain of MED15A. We show that recombinant NPR1 recruits MED15A in an SA-dependent manner, and that MED15A binding reciprocally enhances the affinity of NPR1 for SA. Cryo-electron microscopy and hydrogen-deuterium exchange mass spectrometry reveal that SA and the MED15A KIX domain cooperatively potentiate NPR1-SBD for ternary complex formation by stabilizing its SA-binding core via separate interfaces. We further demonstrate that NIMIN1, a repressor of the SA-NPR1 pathway, antagonizes SA signalling by competing with MED15A for the same NPR1-SBD docking site and allosterically blocking hormone binding. In line with previous genetic evidence establishing a critical role of MED15A in SA signalling, our findings provide a mechanistic resolution to the longstanding question of how SA promotes transcriptional activation during plant immune responses.