Cul2 Is Essential for the Drosophila IMD Signaling-Mediated Antimicrobial Immune Defense

Cullin 2 (Cul2), a core component of the Cullin-RING E3 ubiquitin ligase complex, is integral to regulating distinct biological processes. However, its role in innate immune defenses remains poorly understood. In this study, we investigated the functional significance of Cul2 in the immune deficiency (IMD) signaling-mediated antimicrobial immune reactions in <i>Drosophila melanogaster</i> (fruit fly). We demonstrated that loss-of-function of <i>Cul2</i> led to a marked reduction in antimicrobial peptide induction following bacterial infection, which was associated with increased fly mortality and bacterial load. The proteomic analysis further revealed that loss-of-function of <i>Cul2</i> reduced the expression of Effete (Eff), a key E2 ubiquitin-conjugating enzyme during IMD signaling. Intriguingly, ectopic expression of <i>eff</i> effectively rescued the immune defects caused by loss of <i>Cul2</i>. Taken together, the results of our study underscore the critical role of <i>Cul2</i> in ensuring robust IMD signaling activation, highlighting its importance in the innate immune defense against microbial infection in <i>Drosophila</i>.