Targeted stabilization of MYC2 protein: AI-driven resistance design conquers citrus Huanglongbing

This Highlight discusses the landmark study by Zhao et al. (Science, 2025) that presents a transformative strategy against citrus Huanglongbing (HLB). The work identifies the E3 ubiquitin ligase PUB21 as a central susceptibility (S) factor, degrading the defense regulator MYC2. Crucially, the study harnesses natural resistance (dominant-negative PUB21DN mutant) and pioneers AI-driven design to develop a 14-amino acid peptide (APP3-14). This peptide dually combats HLB by stabilizing MYC2 (inhibiting PUB21) and directly targeting the unculturable pathogen Candidatus Liberibacter asiaticus ( C Las), achieving >90% bacterial reduction in field trials. The research also exposes how a C Las effector (SDE5, Sec-delivered effector 5) hijacks the PUB21-MYC2 axis. This work establishes "defense protein stabilization" as a powerful new paradigm for breeding resistant crops and controlling recalcitrant pathogens, exemplified by the innovative integration of AI in peptide therapeutics for plants. • Key gene PUB21 weakens plant defenses, making citrus vulnerable to Huanglongbing disease. • Natural mutant PUB21DN stops disease by protecting defense proteins from destruction. • AI-designed peptide fights infection by boosting immunity and killing bacteria directly. • Pathogen protein SDE5 speeds up plant defense shutdown, revealing new treatment targets. • Overview:This study tackles citrus Huanglongbing (HLB), a devastating disease caused by Candidatus Liberibacter asiaticus ( C Las). The research focuses on PUB21, a plant gene that promotes disease by breaking down MYC2, a critical defense protein. A natural mutant version, PUB21DN, blocks this process, granting full resistance. Innovatively, an AI-designed 14-amino acid peptide (APP3-14) stabilizes MYC2 and directly targets C Las. The pathogen’s effector protein SDE5 was shown to hijack PUB21 to suppress immunity, exposing vulnerabilities for intervention.