Bacterial lipid effectors subvert host autophagic flux by inducing lysosomal dysfunction

HlyF and CprA, virulence factors from Escherichia coli and Pseudomonas aeruginosa respectively, constitute a previously unrecognized family of cytoplasmic enzymes that drive virulence through the production of outer membrane vesicles (OMVs) enriched in toxic bioactive lipids. Here, we show that OMVs of bacteria producing HlyF/CprA impair host autophagic flux by targeting lysosomal function. Specifically, these OMV-associated lipids disrupt autophagosome-lysosome fusion and induce hallmark features of lysosomal dysfunctions, including defective acidification, cholesterol accumulation, and membrane permeabilization. These lipid-mediated alterations compromise lysosomal integrity and block autophagic degradation. Our findings reveal a novel mechanism by which bacterial lipids subvert lysosomal functions and host clearance pathways. Given the widespread expression of HlyF/CprA homologs across diverse pathogens, this work highlights lipid effectors as key determinants of pathogenesis.