RsaE controls central metabolic pathways.

<p>RsaE regulates, directly or indirectly, the expression of several genes involved in amino acid synthesis, peptides transport, carbohydrate metabolism, and the TCA cycle. RsaE directly regulates the TCA cycle by inhibiting <i>sucD</i> mRNA translation coding for one of the subunits of the succinyl-Coa synthase. It alters the purine biosynthetic pathway via the down-regulation of some enzymes involved in the folate-dependent, one-carbon metabolism. RsaE uses multiple binding sites for the regulation of the <i>opp3BCDFA</i> mRNA expressing an oligopeptide transporter involved in nutrient transport. RsaE pairs directly with sites overlapping the ribosome binding site of the upstream (<i>opp3B</i>) and distal (<i>opp3A</i>) genes from the operon to inhibit their translations. RsaE modulates the intracellular pool of amino acid by down-regulating the expression of an oligopeptide transporter and by up-regulating genes that produce amino acid synthesis enzymes. In some <i>S. aureus</i> strains, RsaE expression is controlled by the <i>agr</i> quorum-sensing system in response to autoinducing peptide (AIP), and it depends on the σ^B regulon. The plain and dashed lines indicate the direct and indirect gene regulations, respectively (red bars: inhibitions, black arrows: stimulations).</p

sRNAs from the <i>S. aureus</i> RNome implicated in bacterial virulence.

<p>Multitasking RNAIII is the effector of quorum sensing to perceive bacterial population density and regulates multiple targets involved in peptidoglycan metabolism, adhesion, exotoxins production, and virulence. RNAIII internally encodes hemolysin δ (blue). RNAIII contains at least three repressor domains (red) containing accessible UCCC motifs that interact, by antisense pairings, with the ribosome binding sites of numerous target mRNAs for translational repression (Tr.R), some triggering endoribonuclease III (RNase III) cleavages to induce target mRNA degradations and irreversible gene expression decay. Translation of at least two exotoxins is activated by RNAIII, one encoded (hlδ), and another (hlα) by translation activation (Tr.A). SprD is expressed from the genome of a converting phage and interacts, by antisense pairings, with the 5′ part of the <i>sbi</i> mRNA encoding an immune evasion molecule. SprD possesses an important role in <i>S. aureus</i> virulence, but the mechanism of its control is yet to be elucidated, with Sbi being only one player among others. The 891-nucleotide long SSR42 affects extracellular virulence expression, hemolysis, neutrophil virulence, and pathogenesis and contains a putative internal ORF. The mechanisms of target regulation remain to be elucidated. The SCCmec-encoded <i>psm-mec</i> RNA suppresses <i>agrA</i> translation and attenuates MRSA virulence, acting as a dual-function RNA regulator.</p

<i>Cis</i>- and <i>trans</i>-acting sRNAs, their corresponding mRNA targets, and physiological consequences.

<p>A non-exhaustive list of <i>S. aureus</i> sRNAs and their experimentally validated targets is shown.</p

Schematic overview of the multiple interactions between sRNAs and transcriptional regulators involved in <i>spa</i> (protein A) and <i>hla</i> (α-hemolysin) expression in <i>S. aureus</i> strain 8325-4.

<p>The arrows indicate the stimulations and the bars, the repressions. The direct effects of two sRNAs on gene expression are indicated in red. RNAIII represses <i>rot</i> and <i>spa</i> translation by direct pairing interactions <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Novick2" target="_blank">[14]</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Geisinger1" target="_blank">[45]</a>. Rot requires SarT to stimulate SarS in the presence of SarA <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Oscarsson1" target="_blank">[92]</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Schmidt2" target="_blank">[120]</a>. In contrast to SarA, Rot and SarS are direct activators of <i>spa</i> expression <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Oscarsson1" target="_blank">[92]</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Gao1" target="_blank">[121]</a>. In the exponential phase of growth, <i>spa</i> transcription is stimulated by Rot and by SarS. In the post-exponential phase, <i>spa</i> transcription and translation are repressed by SarA and RNAIII, respectively, and the direct inactivation of Rot by RNAIII leads to the repression of the Rot and the SarS-dependent transcription activations of <i>spa</i>. <i>hla</i> is up-regulated by SarA and down-regulated by SarS <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Oscarsson2" target="_blank">[93]</a>. Rot and SarT repress <i>hla</i> transcription by a <i>sae</i>-dependent way <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Li1" target="_blank">[94]</a>. In the post-exponential phase of growth, RNAIII enhances <i>hla</i> translation by direct pairings at the <i>hla</i> mRNA 5′UTR and stimulates <i>hla</i> transcription by down-regulating the expression of SarT and Rot. AgrA, the master transcriptional regulator of quorum sensing, stimulates RNAIII expression <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Reyes1" target="_blank">[122]</a> but also represses ArtR expression. ArtR indirectly activates <i>hla</i> transcription by repressing <i>sarT</i> translation <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Xue1" target="_blank">[98]</a>. SarA stimulates the AgrA-dependent expression of RNAIII <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Reyes1" target="_blank">[122]</a>. SarT directly represses SarU which activates <i>agr</i> (RNAIII) transcription <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003767#ppat.1003767-Manna1" target="_blank">[123]</a>.</p

A variety of mechanisms of actions for the <i>S. aureus</i> sRNAs.

<p>(A) <i>Cis</i>-encoded sRNAs bind via perfect complementarities with mRNA targets at the translation initiation sequence, preventing ribosome binding and therefore translation. (B) <i>Trans</i>-acting sRNAs. The <i>trans</i>-encoded sRNAs bind and block the ribosome binding site by interrupted pairings, using one or two hairpin(s) to repress translation initiation. (C) <i>Cis</i>-encoded antisense sRNAs acting in <i>trans</i>. In the SprA1/A1_AS TA module, SprA1_AS prevents SprA1 translation to prevent toxic peptide expression. On the two interacting sRNAs, the <i>cis</i> and <i>trans</i> pairing-regions are indicated in blue and red, respectively.</p