Drosophila Tet mediates the host IMD antibacterial immune defense in a catalytic activity-independent manner

Ten-eleven translocation (Tet) family enzymes are widely recognized for their roles in DNA demethylation via dioxygenase activity. However, increasing evidence indicates that Tet proteins potentially exert non-catalytic functions. Here, we report an undescribed role of Drosophila melanogaster (fruit fly) Tet in mediating the host antibacterial innate immune defense through a mechanism independent of its enzymatic activity. We demonstrate that genetic silencing of Tet in the Drosophila fat body compromises the activation of the immune deficiency (IMD) signaling pathway upon bacterial infection, resulting in defective induction of antimicrobial peptides (AMPs) and increased fly susceptibility. Strikingly, catalytic mutants of Tet still retain normal immune defenses against bacterial pathogens, indicating that its enzymatic activity is dispensable for the Drosophila antibacterial immune defense. Mechanistically, Tet physically associates with Relish (Rel), the nuclear factor kappa B (NF-κB) transcription factor of the IMD signaling pathway, and facilitates the binding of Rel to its downstream AMP genes. Collectively, our findings reveal a catalytic-independent function of Tet in the transcriptional control of Drosophila innate immunity, broadening the understanding of Tet-mediated gene regulation.