Abstract
Listeria monocytogenes is able to colonize human and animal intestinal tracts and to subsequently cross the intestinal barrier, causing systemic infection. For successful establishment of infection, L. monocytogenes must survive the low pH environment of the stomach. L. monocytogenes encodes a functional ArgR, a transcriptional regulator belonging to the ArgR/AhrC arginine repressor family. We aimed at clarifying the specific functions of ArgR in arginine metabolism regulation, and more importantly, in acid tolerance of L. monocytogenes. We showed that ArgR in the presence of 10 mM arginine represses transcription and expression of the argGH and argCJBDF operons, indicating that L. monocytogenes ArgR plays the classical role of ArgR/AhrC family proteins in feedback inhibition of the arginine biosynthetic pathway. Notably, transcription and expression of arcA (encoding arginine deiminase) and sigB (encoding an alternative sigma factor B) were also markedly repressed by ArgR when bacteria were exposed to pH 5.5 in the absence of arginine. However, addition of arginine enabled ArgR to derepress the transcription and expression of these two genes. Electrophoretic mobility shift assays showed that ArgR binds to the putative ARG boxes in the promoter regions of argC, argG, arcA, and sigB. Reporter gene analysis with gfp under control of the argG promoter demonstrated that ArgR was able to activate the argG promoter. Unexpectedly, deletion of argR significantly increased bacterial survival in BHI medium adjusted to pH 3.5 with lactic acid. We conclude that this phenomenon is due to activation of arcA and sigB. Collectively, our results show that L. monocytogenes ArgR finely tunes arginine metabolism through negative transcriptional regulation of the arginine biosynthetic operons and of the catabolic arcA gene in an arginine-independent manner during lactic acid-induced acid stress. ArgR also appears to activate catabolism as well as sigB transcription by anti-repression in an arginine-dependent way.
Highlights
Listeria monocytogenes is a foodborne bacterial pathogen capable of invasion and replication in phagocytic and nonphagocytic cells
The arginine deiminase (ADI) pathway is regulated by an arginine repressor, ArgR, a hexameric protein that belongs to the ArgR/AhrC family of transcriptional regulators involved in regulation of arginine biosynthetic metabolism in a feedback manner (Fulde et al, 2011; Choi et al, 2012; Xiong et al, 2015)
These results suggest that ArgR of L. monocytogenes is a typical arginine repressor which might contribute to transcriptional regulation of arginine metabolism
Summary
Listeria monocytogenes is a foodborne bacterial pathogen capable of invasion and replication in phagocytic and nonphagocytic cells. The ADI pathway consists of three enzymes: ADI, ornithine carbamoyl-transferase and carbamate kinase, which are encoded by arcA, arcB and arcC, respectively The actions of these three proteins convert arginine to ornithine, ammonia and carbon dioxide (Xiong et al, 2015). In the recycling pathway as In bacilli and most other prokaryotes, the acetyl group of N-acetylornithine is effectively transferred to glutamate by an acetyltransferase (ArgJ), making N-acetylglutamate synthase (ArgA), and N-acetylornithinase (ArgE) of the linear pathway redundant (Lu, 2006). This situation is found in L. monocytogenes (Supplementary Figure S1B). ArgR-mediated regulation network has been shown to respond to various environmental stimuli, such as changes in concentration of arginine and other metabolites and fluctuations in pH, temperature, and oxygen tension (Dong et al, 2004; Gruening et al, 2006; Xiong et al, 2015)
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