The functional Mi-2/Foxo complex targets PGRP-SC2 for the Drosophila immune defense against bacterial infection

Innate immunity is orchestrated by an array of conserved signaling pathways and transcriptional regulators. While Forkhead box O (Foxo) has emerged as a pivotal transcription factor in regulating immune homeostasis, its interaction with chromatin remodeling machinery remains poorly defined. Here, we identify the chromatin remodeler Mi-2 as a crucial component of the <i>Drosophila</i> antibacterial immune defense. Silencing of <i>Mi-2</i> abrogates the induction of antimicrobial peptides in adult flies and leads to reduced host survival following systemic bacterial challenge. Co-immunoprecipitation assays demonstrate a physical interaction between endogenous Mi-2 and Foxo in the <i>Drosophila</i> fat body. Of interest, <i>Foxo</i> silencing phenocopies <i>Mi-2</i> knockdown, suggesting a functional interdependence between the two factors. Mechanistically, the Mi-2/Foxo functional complex binds to the 5' flanking region of <i>Peptidoglycan recognition protein SC2</i> (<i>PGRP-SC2</i>), a negative regulator of the immune deficiency (IMD) signaling pathway, to prevent <i>PGRP-SC2</i> expression. Genetic epistasis experiments support a hierarchical relationship, with <i>PGRP-SC2</i> acting downstream of <i>Mi-2</i>/<i>Foxo</i>. Collectively, our findings uncover a previously uncharacterized chromatin-based regulatory mechanism whereby Mi-2 collaborates with Foxo to mediate the antibacterial immune response in <i>Drosophila</i>.