Abstract
Innate immunity in Drosophila melanogaster (fruit fly) relies on intricate transcriptional and post-translational regulatory mechanisms to ensure effective pathogen clearance. Here, we identify the Polycomb repressive deubiquitinase (PR-DUB) complex as a pivotal modulator of the fly antibacterial immune defense. Genetic silencing of calypso (caly) and Additional sex combs (Asx), which encode two key PR-DUB components, renders flies hypersensitive to bacterial infections, accompanied by impaired induction of antimicrobial peptides (AMPs) and dysregulated immune deficiency (IMD) signaling. Mechanistically, Caly/Asx govern the expression of Calcineurin A1 (CanA1), which encodes a calcium/calmodulin-dependent phosphatase essential for AMP inductions. Chromatin immunoprecipitation and luciferase reporter analyses reveal that Caly/Asx directly regulate CanA1 transcription through deubiquitination of mono-ubiquitinated histone H2A (H2Aub1) at the CanA1 promoter. Restoring CanA1 expression alleviates the immune defects of caly- or Asx-silenced flies. Of note, Caly/Asx-H2Aub1-CanA1 regulation occurs in Drosophila hemocytes but not fat bodies for optimal IMD signaling. Collectively, our findings uncover a previously unrecognized role for the PR-DUB complex in Drosophila antibacterial immunity, establishing the Caly/Asx-H2Aub1-CanA1 pathway as a key epigenetic checkpoint that couples chromatin state to immune competence.
