Recognition of pathogens by the host cell is of paramount importance for the initiation of an immune response and clearance of the pathogen. Sensing of the pathogen is mediated by extracellular and intracellular pattern-recognition receptors, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), AIM2-like receptors (ALRs) and RIG-I-like receptors (RLRs). Certain NLRs and ALRs induce the formation of an inflammasome, a cytoplasmic multi-protein complex which drives cell death and the release of the pro-inflammatory cytokines IL-1beta and IL-18. Pathogen-associated ligands must secure entry into the cytoplasm to activate cytoplasmic receptors and the inflammasome; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. We have identified that interferon-inducible proteins can directly target and kill cytoplasmic bacteria. This novel anti-microbial host defense system mediates cytosolic release of bacterial ligands for sensing by pattern-recognition receptors. Our results reveal an important link between cell-autonomous immunity and innate immune sensing pathways in response to bacterial infection.