Pyramiding elite alleles of the genetically linked OsNRAMP5 and OsHMA3 confers low Cd accumulation in rice grains without compromising stress tolerance

Excessive cadmium (Cd) accumulation in rice grains poses a serious threat to food security. Cd uptake by roots and its subsequent transport to grains are mediated by mineral element transporters in rice. Consequently, efforts to reduce Cd accumulation are often accompanied by unintended decreases in essential mineral elements. Achieving a substantial reduction in grain Cd concentrations while maintaining appropriate levels of mineral elements therefore remains a major bottleneck in low-Cd rice breeding. Here, we report that pyramiding elite alleles of OsNRAMP5 and OsHMA3, two key genes encoding Cd transporters, confers low Cd accumulation in grains without inducing sensitivity to manganese (Mn) deficiency in Layandabu (LAA), a tropical japonica rice cultivar. A serine-to-phenylalanine substitution at position 313 in OsNRAMP5^LAA weakens its interaction with OsVAP1-3, a vesicle-associated membrane protein (VAMP)-associated protein that facilitates OsNRAMP5 export from the endoplasmic reticulum (ER) to the plasma membrane. This weakened interaction results in partial retention of OsNRAMP5^LAA in the ER, thereby reducing Cd and Mn uptake. Introgression of the linked OsNRAMP5^LAA and OsHMA3^LAA alleles into the commercial rice cultivar Wushansimiao markedly reduced Cd concentrations in brown rice grown in Cd-contaminated fields without incurring a yield penalty, even under combined heat and low-Mn stress. Thus, our findings provide mechanistic insights into how low-Cd accumulation can be balanced with stress resilience and offer a promising strategy for developing rice cultivars with low-Cd grains and broad environmental adaptability.