Molecular Mimicry Enables Engineering of NLR Immune Receptors with Multi-Recognition

Plants deploy intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors to detect pathogen-secreted virulence effectors and trigger defense responses. NLRs recognize effectors from both adapted and non-adapted pathogens (Dong et al., 2025), either through direct binding or by monitoring effector-induced modifications of host targets (Cesari et al., 2018). Despite these advances, the mechanism by which NLRs evolve new effector-recognition specificities remains a fundamental question in plant immunity. Recently, Gómez de la Cruz et al. (2026) uncovered a novel evolutionary strategy underlying the recognition of the blast fungus effector Pwl2 by the barley NLR MLA3, in which MLA3 acts as a molecular mimic of the effector's virulence target, the heavy metal-associated protein HIPP43 (Zdrzałek et al., 2024; Were et al., 2025). Importantly, the authors successfully transferred this molecular mimicry interface into the wheat stem rust resistance protein SR50, generating a chimeric NLR receptor with dual pathogen-recognition capabilities. The engineered receptor conferred resistance to both wheat stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), and rice blast disease, caused by Magnaporthe oryzae, in transgenic barley, highlighting the potential of this strategy for developing broad-spectrum and durable disease resistance in crops.