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A class of proteins that were discovered to bind the immunosuppressant drug FK506, called FK506-binding proteins (FKBPs), are members of a sub-family of immunophilins. Although they were first identified in human, FKBPs exist in all three domains of life. In this report, a rice <i>FKBP12</i> homolog was first identified as a biotic stress-related gene through suppression subtractive hybridization screening. By ectopically expressing <i>OsFKBP12</i> in the heterologous model plant system, <i>Arabidopsis thaliana</i>, for functional characterization, OsFKBP12 was found to increase susceptibility of the plant to the pathogen, <i>Pseudomonas syringae</i> pv. <i>tomato</i> DC3000 (<i>Pst</i> DC3000). This negative regulatory role of FKBP12 in biotic stress responses was also demonstrated in the <i>AtFKBP12-</i>knockout mutant, which exhibited higher resistance towards <i>Pst</i> DC3000. Furthermore, this higher-plant FKBP12 homolog was also shown to be a negative regulator of salt tolerance. Using yeast two-hybrid tests, an ancient unconventional G-protein, OsYchF1, was identified as an interacting partner of OsFKBP12. OsYchF1 was previously reported as a negative regulator of both biotic and abiotic stresses. Therefore, OsFKBP12 probably also plays negative regulatory roles at the convergence of biotic and abiotic stress response pathways in higher plants.