Disease relevance of sarA

• Background. The Staphylococcus aureus global regulators--agr, sarA, and sae--coordinately control alpha -toxin gene (hla) expression in vitro [1].
• Regulation of Staphylococcus aureus alpha -Toxin Gene (hla) Expression by agr, sarA, and sae In Vitro and in Experimental Infective Endocarditis [1].
• We have cloned the sarA gene, expressed SarA in Escherichia coli and purified the recombinant protein to apparent homogeneity [2].
• In contrast, the autolysis-deficient phenotype of 14-4 was correlated with both increased expression of negative autolysis regulators (arlRS, mgrA, and sarA) and decreased expression of positive regulators (agr RNAII and RNAIII) [3].
• By using this model, we confirmed that mutation of sarA and/or agr results in a reduced capacity to cause both septic arthritis and osteomyelitis [4].

High impact information on sarA

• Studies in experimental endocarditis confirmed the key roles of both sarA and sigB in mediating the antistaphylococcal effects of salicylic acid in vivo [5].
• The sarA locus in Staphylococcus aureus controls the expression of many virulence genes [6].
• The sarA regulatory molecule, SarA, is a 14.7-kDa protein (124 residues) that binds to the promoter region of target genes [6].
• Whereas agr and sarA mutants of RA1 exposed to CPX still displayed increased adhesion to fibronectin, the CPX-triggered response was abolished in the uvs-568 recA mutant, but was restored following complementation with wild type recA [7].
• Analysis of the double sarA/sarR mutant in the early phase of growth reveals its significant role in regulating agr expression as compared with single mutants [8].

Chemical compound and disease context of sarA

• Regulation of Staphylococcus aureus capsular polysaccharide expression by agr and sarA [9].

Biological context of sarA

• In vitro, hla expression was positively modulated by all 3 regulons (sae > agr/sarA > agr and sarA) in both RN6390 and SH1000 backgrounds [1].
• The strain-dependent effects of the msa mutation were similar to those observed previously, which suggests that msa may modulate the production of specific virulence factors through its impact on sarA [10].
• Specifically, the results indicate that, in contrast to NCTC 8325 derivatives, agr plays a limited role in overall regulation of gene expression in UAMS-1, when compared with sarA [11].
• Furthermore, analyses determined that altered expression of sigB and sarA is not responsible for the salicylate-inducible mechanism, and sarA upregulation is associated with the PS(RS) phenotype [12].
• Both genes have similar effects on intrinsic vancomycin resistance, and the salicylate-inducible mechanism is not sigB- or sarA-dependent [12].

Anatomical context of sarA

• These data demonstrate that long-chain 3-oxo-substituted AHLs, such as 3-oxo-C12-HSL, are capable of interacting with the S. aureus cytoplasmic membrane in a saturable, specific manner and at sub-growth-inhibitory concentrations, down-regulating exotoxin production and both sarA and agr expression [13].
• Furthermore, infection of endothelial cells with isogenic mutants of various regulator genes revealed that apoptosis induction was dependent on the global regulator agr and the alternative sigma factor sigB, but not influenced by sarA [14].
• The agr and/or sarA mutants were, nonetheless, fully capable of producing pneumonia and were as proficient as the wild-type strain in stimulating epithelial IL-8 expression, a polymorphonuclear leukocyte chemokine, in airway cells [15].
• We have previously shown that a transposon insertion into the 372-bp sarA gene within the sar locus resulted in decreased expression of several extracellular and cell wall proteins (A. L. Cheung and S. J. Projan, J. Bacteriol. 176:4168-4172, 1994) [16].

Associations of sarA with chemical compounds

• In addition, salicylate induction upregulates two antibiotic target genes and downregulates a multidrug efflux pump gene repressor (mgrA) and sarR, which represses a gene (sarA) important for intrinsic antimicrobial resistance [17].
• Inactivation of the same protease genes in a sarA mutant of 8325-4 resulted in a 10- to 20-fold increase in cell-bound protein A. As the serine protease requires aureolysin to be activated, it can thus be concluded that the serine protease is the most important protease in the release of cell-bound FnBPs and protein A [18].
• The addition of heparin rescued biofilm formation of hla, ica, and sarA mutants [19].
• The sarV mutant was more resistant to Triton X-100 and penicillin-induced lysis compared to the wild type and the sarA mutant, whereas hyperexpression of sarV in the parental strain or the sarV mutant rendered the resultant strain highly susceptible to lysis [20].
• The phenotypic switching correlates with a dramatic increase in the number of IS256 copies in the chromosomes of biofilm-negative variants, as well as with an augmented IS256 insertion frequency into the icaC and the sarA genes [21].

Regulatory relationships of sarA

• However, the pathway by which the sarA locus downregulates spa expression is sarS independent [22].
• Although sarA up-regulated and agr down-regulated both fnbA expression and fibronectin binding in vitro and in vivo, fnbA expression was positively regulated in the absence of both global regulators [23].
• Additionally, the sarA P3 promoter activity of the parental strain was induced to a higher level in response to pH 5.5 than was that of the rsbU or rsbV mutant, indicating that RsbU is the major activator of the sigma(B) response to acid stress [24].
• In contrast, hla transcription was enhanced in the sarA sarT mutant compared with the single sarA mutant [25].
• Transcriptional gene fusion and Western analysis revealed that sarA up-regulates both toxic shock syndrome toxin 1 gene (tst) expression and staphylococcal enterotoxin B production, respectively [26].

Other interactions of sarA

• On the other hand, the relative increase in sarS transcription upon the inactivation of sarA was 15-fold higher in 8325-4 than in strain V8 [27].
• Coordinated and differential control of aureolysin (aur) and serine protease (sspA) transcription in Staphylococcus aureus by sarA, rot and agr (RNAIII) [28].
• To identify candidate regulatory pathway(s) linking drug exposure to up-regulation of fnbB, we disrupted the global response regulators agr, sarA, and recA in the highly quinolone-resistant strain RA1 [7].
• The sequence encompassing ORF3 located upstream of sarA was found to be essential for the activation of fnbA transcription [29].
• The arl mutation did not change spa expression in an agrA mutant or in a sarA mutant, suggesting that both the sarA and the agr loci are required for the action of arl on spa [30].

Analytical, diagnostic and therapeutic context of sarA

• Northern blot analyses indicated that the arl mutation increased the synthesis of both RNA II and RNA III, but decreased sarA transcription [30].
• Accordingly, real-time PCR showed that the mutation in the sarA gene resulted in downregulation of the ica operon transcription [31].
• Although a DNA fragment encompassing the sarA transcript plus a 189-bp upstream region was sufficient for agr expression, complementation analysis revealed that the sarB transcript was the most effective in augmenting agr transcription as determined by RNAII and RNAIII transcription and gel retardation assays with the P2 and P3 promoters of agr [32].

References