Table 1.
RNA regulators of Yersinia important for virulence.
| Regulators | Mechanisms/Targets | Virulence-associated processes | Regulation | References |
|---|---|---|---|---|
| Trans-ENCODED ncRNA | ||||
| CsrB/CsrC | Small structured RNAs with multiple GGA sequences that bind and sequester CsrA, Hfq-dependent | Control of RovM, RovA, InvA/PsaA adhesins, T3SS/Yops, host-adapted metabolism, motility, carbon metabolism, stress resistance | Controlled by BarA/UvrY, PhoP/PhoQ, Crp, short chain fatty acids, acidic pH, antimicrobial peptides | (Heroven et al., 2008, 2012; Romeo et al., 2013; Bücker et al., 2014; LeGrand et al., 2015; Kusmierek and Dersch, 2017; Ozturk et al., 2017) |
| RybB | Hfq-dependent sRNA | Induced in the lung and spleen during infection with Y. pestis biovar microtus | Temperature and growth phase-dependent | (Koo et al., 2011; Yan et al., 2013; Nuss et al., 2015, 2017a) |
| RyhB1/RyhB2 | Homologous Hfq-dependent sRNAs | ryhB1 and ryhB2 have a small influence on virulence in Y. pestis biovar microtus and Y. pseudotuberculosis | Increased during iron starvation, induced in the lung and spleen during infection with Y. pestis biovar microtus, and induced in Peyer's patches of mice, they depend on growth phase, they are controlled by the regulator Fur, degraded by PNPase | (Deng et al., 2012, 2014; Yan et al., 2013; Nuss et al., 2017a) |
| GlmZ/GlmY | Homologous sRNAs, GlmZ activates glmS mRNA translation by an anti-antisense mechanism, GlmY acts upstream of GlmZ and positively regulates glmS by antagonizing GlmZ RNA inactivation | Control amino-sugar metabolism, GlmY/GlmZ control glmS, which encodes the enzyme glutamine synthase necessary for the synthesis of N-acetylglucosamine-6-P, which is used for cell wall biosynthesis | Regulated by RNase E and Hfq | (Görke and Vogel, 2008; Urban and Vogel, 2008; Nuss et al., 2017a) |
| SsrA/tmRNA | A-site of stalled ribosomes, binds together with SmpB to stalled ribosomes by mimicking a tRNA and mRNA, which replaces incomplete/truncated transcripts within stalled ribosomes | Rescues stalled ribosomes, holds the translation machinery in the operation mode | Induced in the lung and spleen during infection with Y. pestis biovar microtus | (Okan et al., 2006, 2010; Yan et al., 2013) |
| SgrS | SgrS activates synthesis of the phosphatase YigL in a translation-independent fashion the SgrS RNA targets the pldB mRNA and blocks sustained 5'- to 3'- endonucleolytic turnover of the pldB-yigL transcript by RNase E | Phospho sugar stress, SgrS-mediated increase of phosphatase YigL leads to the dephosphorylation of the accumulated sugars and facilitates their export by efflux systems | Glucose-6-P-responsive, accumulation of phospho sugars is toxic and activates SgrS RNA through the SgrR transcription factor | (Vanderpool and Gottesman, 2004; Papenfort et al., 2012, 2013; Bobrovskyy and Vanderpool, 2014, 2016; Nuss et al., 2017a) |
| Ysr29 | – | General stress response (GroEL, DnaK, UreC, S/RpsA, Gst, AhpC, Rrf), required for stress response and full virulence of Y. pseudotuberculosis | Temperature and growth phase-dependent | (Koo et al., 2011) |
| Ysr35 | – | Required for full virulence of Y. pseudotuberculosis and Y. pestis, controls several general stress response factors such as GroEL, DnaK, the peroxidase AhpC and the translation factors RpsA and Rrf | Temperature-induced | (Koo et al., 2011) |
| Ysr141 | – | Influences expression and secretion of T3SS/Yop components and the major regulator LcrF, modulates host immune defense, has direct influence on YopJ translation | – | (Schiano et al., 2014) |
| Ysr170 | – | Important for intracellular replication of Y. pestis in cultured macrophages | – | (Li et al., 2016) |
| ANTISENSE RNA | ||||
| CopA | Complementary to the replicase gene repA of the Yersinia virulence plasmid | Repression of the replication of the virulence plasmid pYV, repression of repA mRNA translation/stability, reduces expression of the T3SS/Yop components | Downregulated during colonization of the Peyer's patches | (Qu et al., 2012; Wang et al., 2016) |
| RNA THERMOMETER | ||||
| Ail | 5′-UTR of the adhesin gene ail | Stem-loop structure restricts access of ribosomes to the ribosome binding site at 25°C but not at 37°C, regulation of the expression of the cell attachment and invasion outer membrane protein Ail | Temperature-induced | (Rhigetti et al., 2016) |
| cnfY | 5′-UTR of the toxin gene cnfY | A stem-loop structure restricts access of ribosomes to the ribosome binding site at 25°C but not at 37°C, regulation of the expression of the cytotoxic necrotizing factor CNFY | Temperature-induced, controlled by csrA, crp | (Schweer et al., 2013; Rhigetti et al., 2016) |
| lcrF | ysw-lcrF intergenic region, FourU RNA thermometer | A two stem-loop structure restricts access of ribosome to the ribosome binding site at 25°C but not at 37°C, proper function required for expression of the T3SS/yop genes and virulence | Temperature-induced, iron limitation, and oxidative stress, controlled by the transcription factors YmoA, RcsB, IscR | (Hoe and Goguen, 1993; Böhme et al., 2012; Schwiesow et al., 2015; Rhigetti et al., 2016) |
| katA | 5′-UTR of the katalase gene katA | Resistance against oxidative stress | Thermally induced structural changes liberate the ribosomal binding site, induced by oxidative stress | (Rhigetti et al., 2016) |
| sodA | 5′-UTR of the superoxide dismutase gene sodA | Resistance against oxidative stress | Thermally induced structural changes liberate the ribosomal binding site, induced by oxidative stress | (Rhigetti et al., 2016) |
| sodB | 5′-UTR of the superoxide dismutase gene sodB | Resistance against oxidative stress | Thermally induced structural changes liberate the ribosomal binding site, induced by oxidative stress | (Rhigetti et al., 2016) |
| sodC | 5′-UTR of the superoxide dismutase gene sodC | Resistance against oxidative stress | Thermally induced structural changes liberate the ribosomal binding site, induced by oxidative stress | (Rhigetti et al., 2016) |
| RIBOSWITCH | ||||
| mgtA/corA | Mg2+ binding RNA secondary structure in the 5′-UTR of the Mg2+ transporter gene mgtA, Mg2+ binding initiates early Rho-independent termination of mgtA transcription through conformational changes in the RNA | This riboswitch regulates Mg2+ uptake, essential for survival and replication of macrophages | mgtA expression is induced under high Mg2+ concentrations | (Korth and Sigel, 2012; Nuss et al., 2015) |
| RNA-BINDING PROTEINS | ||||
| CsrA | CsrA is a global RNA binding protein of the carbon storage regulator system. It interacts with single-stranded GGA motifs within stem-loop structures of mRNAs or the regulatory RNAs CsrB and CsrC, and modulates translation efficiency and stability of mRNAs and regulatory RNAs | CsrA controls multiple virulence- and fitness-relevant traits, e.g., motility, adhesion and invasion factors (YadA, InvA, PsaA), T3SS/Yops, regulatory proteins such as RovM and RovA, various metabolic functions (carbon metabolism), resistance against environmental stresses | CsrA function is controlled by the regulatory RNAs CsrB and CsrC, induced during stationary phase | (Heroven et al., 2008, 2012; Bücker et al., 2014; LeGrand et al., 2015; Willias et al., 2015) |
| Hfq | Hfq is a global RNA binding protein, preferential binding to AU-rich motifs, interacts with multiple regulatory RNAs and mRNAs, Hfq acts as an RNA chaperone, which enhances and stabilizes interaction of regulatory RNAs with target mRNAs | Loss of the hfq gene affects multiple virulence-related traits, e.g. expression of outer membrane adhesins, biofilm formation and cyclic-di-GMP levels, lipid A structure, outer membrane vesicle synthesis, and motility | Induced during stationary phase, dependent on temperature | (Geng et al., 2009; Schiano et al., 2010; Bellows et al., 2012; Rempe et al., 2012; Schiano and Lathem, 2012; Eddy et al., 2014; Kakoschke et al., 2014, 2016; Nuss et al., 2015; Leskinen et al., 2017) |
| SmpB | SmpB is a specific RNA binding protein that interacts with the A site of ribosomes together with SsrA, SmpB assists SsrA interaction with stalled ribosomes to rescue the translation machinery on mRNAs from truncated transcripts without a stop codon | The SmpB/SsrA system influences ysc/yop expression and type III secretion, affects resistance against environmental stresses experienced within phagocytic cells (e.g., oxidative, nitrosative and acidic stress) | Upregulated during infection with Y. pestis biovar Microtus in the lungs | (Okan et al., 2006, 2010) |
| YopD | RNA-binding protein, translocator protein, interaction partner of the chaperone LcrH and the protein LcrQ (YscM1 and YscM2 in Y. enterocolitica), interacts with 5′-UTRs of ysc/yop mRNAs, binds to ribosomes, RNA-binding mechanism and ribosomal interaction partner are unknown | Influences expression of the ysc/yop genes, Ca2+-blind/independent expression of the T3SS | LcrF-dependent expression, temperature-regulated, host cell contact-induced | (Williams and Straley, 1998; Anderson et al., 2002; Cambronne and Schneewind, 2002; Chen and Anderson, 2011) |
| RNases | ||||
| RNase E | RNA degradation, endonuclease, cleaves RNA substrates in single-stranded regions followed by a stable stem-loop structure, RNase E is part of the degradosome, a multiprotein complex that includes PNPase | RNase E influences secretion of the T3SS effectors | – | (Yang et al., 2008) |
| PNPase | RNA degradation, exonuclease, cleaves RNA substrates from the 5'- and 3'-end. PNPase is part of the degradosome, a multiprotein complex, and cooperates with RNase E | PNPase influences secretion of the T3SS effectors, influences resistance against oxidative stress and growth in the cold | – | (Rosenzweig et al., 2005, 2007; Henry et al., 2012; Rosenzweig and Chopra, 2013) |
| YbeY | RNA decay, processing of 3′-ends of the 16S rRNA, responsible for the late stage 70S ribosome quality control | Pleiotropic, controls many virulence-relevant traits, including acid stress resistance, cell adhesion/invasion properties and T3SS, controls regulatory RNAs CsrB and CsrC | – | (Leskinen et al., 2015) |
| RNase III | RNA decay, binds and cleaves double-stranded RNA, processing of ribosomal RNA precursors and of some mRNAs | Affects abundance of the RyhB2 transcript | – | (Deng et al., 2014) |