Type I interferon remodels lysosome function and modifies intestinal epithelial defense.

Organelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogen led us to discover that type I IFN (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity, and proteomic profile of lysosomes. Proteomic and genetic analyses revealed that multiple IFN-I-stimulated genes including , , and contribute to lysosome acidification. IFN-I-dependent lysosome acidification was associated with elevated intracellular virulence gene expression, rupture of the -containing vacuole, and host cell death. Moreover, IFN-I signaling promoted in vivo pathogenesis in the intestinal epithelium where initiates infection, indicating that IFN-I signaling can modify innate defense in the epithelial compartment. We propose that IFN-I control of lysosome function broadly impacts host defense against diverse viral and microbial pathogens.