3'UTR-derived small RNA couples acid resistance to metabolic reprogramming of Salmonella within 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 pathogen Salmonella is expression of the arginine decarboxylase AdiA. While AdiA confers acid resistance via an H+-consuming reaction, we discover that the 3'-untranslated region (UTR) of adiA mRNA is processed by RNase E into a regulatory small RNA, AdiZ. Through RNA-RNA interactome profiling and transcriptomic analysis, followed by in vitro structural probing and in vivo validations, we demonstrate that AdiZ directly base-pairs with and negatively regulates ptsG, pykF, and dmsA mRNAs involved in glucose uptake, glycolysis, and anaerobic respiration, respectively. Intriguingly, AdiZ is induced and facilitates Salmonella survival 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 of Salmonella in the host intracellular niches. HIGHLIGHTSO_LISalmonella adiA transcript expresses both acid resistance enzyme and sRNA AdiZ C_LIO_LIAdiZ derived from the adiA 3'UTR is induced under an acidic and anaerobic condition C_LIO_LIAdiZ base-pairs with mRNAs to modulate glucose metabolism and anaerobic respiration C_LIO_LIAdiZ promotes Salmonella survival in acidic and hypoxic macrophage vacuoles C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/658255v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@10aec22org.highwire.dtl.DTLVardef@14b5f2org.highwire.dtl.DTLVardef@1b53c8dorg.highwire.dtl.DTLVardef@19a8540_HPS_FORMAT_FIGEXP M_FIG C_FIG