BAP1 as a novel regulator of type I interferon signaling through transcriptional control of key response machinery components

Type I interferon (IFN-I) signaling is critical for dual immunity, defending against microbial infections and augmenting anti-tumor immune responses. Research in the past few decades have identified the key machinery components and over 300 interferon-stimulated genes (ISGs) that comprise the IFN-I signaling network. While cascade amplification mechanisms ensure robust pathway activation, appropriate expression of signaling components is essential for maintaining pathway sensitivity, enabling efficient signal amplification, and providing adequate host responses. Here, we identified BRCA1-associated protein-1 (BAP1) as a positive regulator of the IFN-I signaling pathway through a genome-wide CRISPR/Cas9 screen in murine macrophage Raw264.7 cells stimulated with cGAMP. We confirmed both the enzymatic activity and nuclear localization of BAP1 were essential for this regulation. Our findings reveal that BAP1 regulates a broad transcriptional program essential for IFN-I responses, including IFNAR1 and IFNAR2 . BAP1 deficient cells failed to mount an effective IFN-I response, showing markedly reduced ISGs and resulting in uncontrolled viral replication. These findings together highlight an essential role of BAP1 in controlling IFN-I signaling and antiviral responses.