**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** ENGINEERING CROPS WITH EFFECTIVE AND LONG-LASTING PATHOGEN RESISTANCE IS ESSENTIAL FOR A SUSTAINABLE AND SECURE FOOD SUPPLY. UNDERSTANDING HOW THE PLANT IMMUNE SYSTEM WORKS AT THE MOLECULAR LEVEL IS CRUCIAL TO IDENTIFY GENES OF INTEREST FOR BREEDING AND GENETIC ENGINEERING EFFORTS TO GENERATE DISEASE-RESISTANT CROPS. TARGETED DEGRADATION OF PROTEINS VIA A CELLULAR PATHWAY CALLED THE UBIQUITIN-PROTEASOME SYSTEM (UPS) IS KEY FOR REGULATING THE PLANT IMMUNE SYSTEM AND IS THEREFORE A VITAL PROCESS FOR PLANT DEFENSE AGAINST PATHOGENS. SPECIFIC RECOGNITION OF TARGET PROTEINS IS AN ESSENTIAL ASPECT OF THIS PATHWAY AND IS FACILITATED BY UBIQUITIN LIGASE (E3) ENZYMES. PRACTICALLY, LOSS OR GAIN-OF-FUNCTION MUTATIONS FOR E3S/E3 TARGET PROTEINS INVOLVED IN IMMUNITY CAN FINE-TUNE THE ROBUSTNESS OF PLANT DEFENSE RESPONSES AND IMPROVE PATHOGEN RESISTANCE.HOWEVER, TWO MAJOR KNOWLEDGE GAPS PREVENT EXTENSIVE ENGINEERING OF THE UPS FOR CROP IMPROVEMENT: (1) THE BIOLOGICAL FUNCTION OF FEW PLANT E3S HAS BEEN CHARACTERIZED, AND (2) THE MOLECULAR MECHANISMS BY WHICH E3S ACCURATELY RECOGNIZE PROTEINS THAT ARE TO BE DEGRADED ARE NOT WELL UNDERSTOOD. TO ADDRESS THESE KNOWLEDGE GAPS, THIS STUDY WILL UTILIZE METHODS BASED IN THE GLOBAL STUDY OF PLANT PROTEINS AND PROTEIN STRUCTURE TO (1) IDENTIFY E3S/E3 TARGETS INVOLVED IN PLANT IMMUNITY, (2) DISSECT THE MECHANISM(S) REGULATING E3-MEDIATED PLANT IMMUNE RECEPTOR DEGRADATION, AND (3) VALIDATE THESE FINDINGS IN TOMATO AND THE MODEL ORGANISM ARABIDOPSIS THALIANA TO CHARACTERIZE THEIR CONTRIBUTION TO BACTERIAL AND FUNGAL PATHOGEN RESISTANCE. THESE RESULTS WILL BE BROADLY TRANSLATED ACROSS CROP PLANTS AND WILL IDENTIFY CANDIDATE E3S/E3 TARGETS FOR GENETIC EDITING TO FINE-TUNE IMMUNITY AND PROVIDE INSIGHT ON HOW PLANTS REGULATE IMMUNITY BY MODULATING IMMUNE RECEPTOR DEGRADATION. ULTIMATELY, THIS WILL ENABLE MORE INFORMED GENE EDITING TO PRODUCE CROPS WITH EFFECTIVE AND LONG-LASTING PATHOGEN RESISTANCE.