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A Trans-Acting Leader RNA from a Salmonella Virulence Gene

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A Trans-Acting Leader RNA from a Salmonella Virulence Gene A trans-acting leader RNA from a Salmonella virulence gene Eunna Choia,1, Yoontak Hana,1, Yong-Joon Chob,1, Daesil Namc, and Eun-Jin Leea,2 aDepartment of Genetic Engineering, Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University, Yongin 17104, South Korea; bUnit of Antarctic K-Route Expedition, Korea Polar Research Institute, Incheon 21990, South Korea; and cDivision of Microbiology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Suwon 16419, South Korea Edited by Susan Gottesman, National Institutes of Health, Bethesda, MD, and approved August 10, 2017 (received for review April 3, 2017) Bacteria use flagella to move toward nutrients, find its host, or membrane potential (7). In addition, previous transcriptomic retract from toxic substances. Because bacterial flagellum is one of analysis revealed that mRNA levels of many genes involved in the ligands that activate the host innate immune system, its flagella machinery, including the fljB and fliC flagellin genes, synthesis should be tightly regulated during host infection, which strongly decreased when Salmonella is inside macrophages (8), is largely unknown. Here, we report that a bacterial leader mRNA implicating that flagella-based motility may not be required for from the mgtCBR virulence operon in the intracellular pathogen intramacrophage survival. However, it has been unknown how Salmonella enterica serovar Typhimurium binds to the fljB coding Salmonella achieves such down-regulation of flagellar genes region of mRNAs in the fljBA operon encoding the FljB phase 2 fla- during infection. Here, we report that a leader RNA originated gellin, a main component of bacterial flagella and the FljA repressor from the Salmonella mgtCBR virulence operon mediates down- for the FliC phase 1 flagellin, and degrades fljBA mRNAsinanRNase regulation of one of two flagellin genes inside macrophages. E-dependent fashion during infection. A nucleotide substitution of In the intracellular pathogen Salmonella enterica serovar Typhimurium, the mgtCBR operon encodes the MgtC viru- the fljB flagellin gene that prevents the mgtC leader RNA-mediated + lence protein, the MgtB Mg2 transporter, and the MgtR pep- down-regulation increases the fljB-encoded flagellin synthesis, lead- tide regulator for MgtC proteolysis (9–12). The PhoP/PhoQ ing to a hypermotile phenotype inside macrophages. Moreover, the two-component system controls transcription initiation of the fljB nucleotide substitution renders Salmonella hypervirulent, indi- mgtCBR operon from a single promoter upstream of the mgtC + MICROBIOLOGY cating that FljB-based motility must be compromised in the phago- gene in response to low Mg2 , mildly acidic pH, or antimicrobial somal compartment where Salmonella resides. This suggests that peptides (13–16). After transcription is initiated, the 296-nt-long this pathogen promotes pathogenicity by producing a virulence pro- leader region of the mgtCBR operon mediates further induction tein and limits locomotion by a trans-acting leader RNA from the of the mgtC gene inside macrophages in response to high ATP same virulence gene during infection. and low levels of charged tRNAPro (17–20), allowing the mgtC gene to be one of the highly expressed genes inside macrophages flagellin | mgtC | trans-acting leader RNA (8). Within the mgtCBR leader region, two short ORFs, mgtM and mgtP, enable the leader to sense and respond to respective Pro he bacterial flagellum is a long filamentous structure that is ATP- and charged tRNA signals by a mechanism similar to Tattached to the membrane and enables a bacterium to move that found in transcription attenuation (17–19). This mechanism toward nutrients or to escape from toxic chemicals (1). However, involves coupling between transcription of the mgtCBR leader during host infection, the bacterial flagellum could be dangerous region and translation of each ORF located in the leader, which for survival if it is recognized by the host innate immune system controls the formation of adjacent attenuator stem-loops pre- venting transcription elongation into the downstream coding as a ligand to elicit an immune response (2). Therefore, synthesis or assembly of flagella must be tightly regulated for a pathogen. The major structural component of flagella is thousands of Significance copies of flagellin monomer proteins, which are encoded by two different loci, fljB and fliC, for the intracellular pathogen Sal- The intracellular pathogen Salmonella enterica serovar Typhi- monella enterica serovar Typhimurium (1). Depending on which murium must move toward nutrients to obtain food. However, flagellin genes are expressed, Salmonella displays completely at the same time, it has to evade the host immune system. different antigenic properties that might be advantageous for this Because bacterial flagella are required for both bacterial pathogen to evade the host immune system. This so-called an- movement and immune detection, production of flagella must tigenic phase variation is mediated by an inversion event of a be tightly regulated during infection. Here, we establish that particular DNA region, which includes the hin gene encoding a Salmonella produces a leader RNA from the mgtCBR virulence recombinase and the promoter region of the fljBA operon operon and degrades mRNAs of the fljB phase 2 flagellin gene during infection. Our finding indicates a direct link between a encoding the FljB phase 2 flagellin and FljA, a repressor protein virulence determinant and motility via a trans-acting leader for the distally located FliC flagellin (3, 4) (Fig. 1A). When the RNA derived from the virulence determinant gene in a given DNA region is oriented as illustrated in Fig. 1A, the fljB and fljA host environment. genes are expressed, and, as a result, Salmonella possesses FljB- polymerized flagella on its surface and expression of the other Author contributions: E.-J.L. designed research; E.C., Y.H., Y.-J.C., and D.N. performed fliC flagellin gene is repressed by the FljA repressor at the research; Y.-J.C. and E.-J.L. analyzed data; and E.-J.L. wrote the paper. posttranscriptional level (5) (Fig. 1A). However, when the DNA The authors declare no conflict of interest. region is switched into the opposite orientation by the Hin This article is a PNAS Direct Submission. recombinase at low frequency (6), the promoter region of the Data deposition: The data reported in this paper have been deposited in the Gene Ex- fljBA operon is flipped and the fljB and fljA genes are not pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession nos. expressed and thus Salmonella produces the FliC flagellin proteins. GSE85678 and GSE100414). Several lines of observations were reported that expression of 1E.C., Y.H., and Y.-J.C. contributed equally to this work. flagellar genes might be down-regulated during infection. In 2To whom correspondence should be addressed. Email: [email protected]. uropathogenic Escherichia coli, the virulence regulator PhoP This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. represses FliC flagellin production and motility by decreasing 1073/pnas.1705437114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1705437114 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 radiolabeled DNA probe corresponding to the mgtCBR leader region (22). This is probably due to the presence of the attenu- ator stem-loop structures that prevent transcription elongation within the mgtCBR leader region (17–19, 23) (Fig. S1). In this paper, we report that one of the smallest transcripts of the mgtCBR leader region functions as a trans-acting ribor- egulator and decreases amounts of the FljB flagellin during in- fection. The decrease in flagellin production by the mgtC leader RNA is required for Salmonella’s pathogenicity because the fljB substitution that prevents the mgtC leader-mediated fljB down- regulation renders Salmonella hypervirulent. Our data suggest that Salmonella’s motility powered by FljB flagella must be re- stricted during the course of infection. Results The mgtC Leader RNA Down-Regulates fljB and fljA mRNA Encoding the Salmonella Phase 2 Flagellin Operon. Previous Northern blot analysis using a DNA probe corresponding to the leader region of the mgtCBR operon detected multiple short transcripts in + RNA samples prepared from Salmonella grown in low Mg2 , which activates transcription from the PhoP-dependent mgtC promoter (22). An abundance and size of transcripts led us to wonder whether these short transcripts from the mgtC leader region might have a regulatory role as a trans-acting RNA else- where in the chromosome. To explore this, we constructed a Salmonella strain harboring a plasmid that expresses the smallest size of RNA fragments corresponding to nucleotides 1–113 in the mgtC leader from an arabinose-inducible promoter or the plasmid vector. [Please note that the nucleotide position at 113 is located just beyond the stem-loop B structure (Fig. 1A and Fig. Fig. 1. Regulation of the fljBA phase 2 flagellin operon by the trans-acting S1).] Then, we compared RNA profiles of the mgtC leader- and mgtCBR leader RNA. (A)InlowMg2+, the phosphorylated PhoP controls tran- the vector-expressing Salmonella after arabinose induction for scription of the mgtCBR virulence operon and generates full-length polycistronic 15 min. Surprisingly, only two mRNAs were significantly down- mRNA messages, harboring the 296-nt leader RNA with two short ORFs (mgtM regulated
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