3′UTR-derived small RNA couples acid resistance to metabolic reprogramming ofSalmonellawithin macrophages

Acid resistance is crucial for enterobacteria to withstand host acidic environments during infection, including the gastrointestinal tract and macrophage phagosomes. A key acid resistance mechanism of the facultative intracellular pathogenSalmonellais expression of the arginine decarboxylase AdiA. While AdiA confers acid resistance via an H⁺-consuming reaction, we discover that the 3′-untranslated region (UTR) ofadiAmRNA is processed by RNase E into a regulatory small RNA, AdiZ. Through RNA-RNA interactome profiling and transcriptomic analysis, followed byin vitrostructural probing andin vivovalidations, we demonstrate that AdiZ directly base-pairs with and negatively regulatesptsG,pykF,anddmsAmRNAs involved in glucose uptake, glycolysis, and anaerobic respiration, respectively. Intriguingly, AdiZ is induced and facilitatesSalmonellasurvival within macrophages, where acidic and hypoxic stresses prevail. Thus, simultaneous expression of AdiA and AdiZ from a single mRNA ties arginine-dependent acid resistance to metabolic reprogramming ofSalmonellain the host intracellular niches.