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Gene Review

sarA  -  accessory regulator A

Staphylococcus aureus RF122

 
 
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Disease relevance of sarA

 

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

 

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

  1. Regulation of Staphylococcus aureus alpha -Toxin Gene (hla) Expression by agr, sarA, and sae In Vitro and in Experimental Infective Endocarditis. Xiong, Y.Q., Willard, J., Yeaman, M.R., Cheung, A.L., Bayer, A.S. J. Infect. Dis. (2006) [Pubmed]
  2. Characterization of the SarA virulence gene regulator of Staphylococcus aureus. Rechtin, T.M., Gillaspy, A.F., Schumacher, M.A., Brennan, R.G., Smeltzer, M.S., Hurlburt, B.K. Mol. Microbiol. (1999) [Pubmed]
  3. Transcriptomic and functional analysis of an autolysis-deficient, teicoplanin-resistant derivative of methicillin-resistant Staphylococcus aureus. Renzoni, A., Barras, C., François, P., Charbonnier, Y., Huggler, E., Garzoni, C., Kelley, W.L., Majcherczyk, P., Schrenzel, J., Lew, D.P., Vaudaux, P. Antimicrob. Agents Chemother. (2006) [Pubmed]
  4. Role of sarA in the pathogenesis of Staphylococcus aureus musculoskeletal infection. Blevins, J.S., Elasri, M.O., Allmendinger, S.D., Beenken, K.E., Skinner, R.A., Thomas, J.R., Smeltzer, M.S. Infect. Immun. (2003) [Pubmed]
  5. Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus. Kupferwasser, L.I., Yeaman, M.R., Nast, C.C., Kupferwasser, D., Xiong, Y.Q., Palma, M., Cheung, A.L., Bayer, A.S. J. Clin. Invest. (2003) [Pubmed]
  6. Structural and function analyses of the global regulatory protein SarA from Staphylococcus aureus. Liu, Y., Manna, A.C., Pan, C.H., Kriksunov, I.A., Thiel, D.J., Cheung, A.L., Zhang, G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. A recA-LexA-dependent pathway mediates ciprofloxacin-induced fibronectin binding in Staphylococcus aureus. Bisognano, C., Kelley, W.L., Estoppey, T., Francois, P., Schrenzel, J., Li, D., Lew, D.P., Hooper, D.C., Cheung, A.L., Vaudaux, P. J. Biol. Chem. (2004) [Pubmed]
  8. Transcriptional regulation of the agr locus and the identification of DNA binding residues of the global regulatory protein SarR in Staphylococcus aureus. Manna, A.C., Cheung, A.L. Mol. Microbiol. (2006) [Pubmed]
  9. Regulation of Staphylococcus aureus capsular polysaccharide expression by agr and sarA. Luong, T., Sau, S., Gomez, M., Lee, J.C., Lee, C.Y. Infect. Immun. (2002) [Pubmed]
  10. Identification and characterization of msa (SA1233), a gene involved in expression of SarA and several virulence factors in Staphylococcus aureus. Sambanthamoorthy, K., Smeltzer, M.S., Elasri, M.O. Microbiology (Reading, Engl.) (2006) [Pubmed]
  11. Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390. Cassat, J., Dunman, P.M., Murphy, E., Projan, S.J., Beenken, K.E., Palm, K.J., Yang, S.J., Rice, K.C., Bayles, K.W., Smeltzer, M.S. Microbiology (Reading, Engl.) (2006) [Pubmed]
  12. Contributions of sigB and sarA to distinct multiple antimicrobial resistance mechanisms of Staphylococcus aureus. Riordan, J.T., O'Leary, J.O., Gustafson, J.E. Int. J. Antimicrob. Agents (2006) [Pubmed]
  13. N-acylhomoserine lactones antagonize virulence gene expression and quorum sensing in Staphylococcus aureus. Qazi, S., Middleton, B., Muharram, S.H., Cockayne, A., Hill, P., O'Shea, P., Chhabra, S.R., Cámara, M., Williams, P. Infect. Immun. (2006) [Pubmed]
  14. Multiple virulence factors are required for Staphylococcus aureus-induced apoptosis in endothelial cells. Haslinger-Löffler, B., Kahl, B.C., Grundmeier, M., Strangfeld, K., Wagner, B., Fischer, U., Cheung, A.L., Peters, G., Schulze-Osthoff, K., Sinha, B. Cell. Microbiol. (2005) [Pubmed]
  15. Staphylococcus aureus agr and sarA functions are required for invasive infection but not inflammatory responses in the lung. Heyer, G., Saba, S., Adamo, R., Rush, W., Soong, G., Cheung, A., Prince, A. Infect. Immun. (2002) [Pubmed]
  16. Characterization of the sar locus and its interaction with agr in Staphylococcus aureus. Heinrichs, J.H., Bayer, M.G., Cheung, A.L. J. Bacteriol. (1996) [Pubmed]
  17. Response of Staphylococcus aureus to Salicylate Challenge. Riordan, J.T., Muthaiyan, A., Van Voorhies, W., Price, C.T., Graham, J.E., Wilkinson, B.J., Gustafson, J.E. J. Bacteriol. (2007) [Pubmed]
  18. Decreased amounts of cell wall-associated protein A and fibronectin-binding proteins in Staphylococcus aureus sarA mutants due to up-regulation of extracellular proteases. Karlsson, A., Saravia-Otten, P., Tegmark, K., Morfeldt, E., Arvidson, S. Infect. Immun. (2001) [Pubmed]
  19. Heparin stimulates Staphylococcus aureus biofilm formation. Shanks, R.M., Donegan, N.P., Graber, M.L., Buckingham, S.E., Zegans, M.E., Cheung, A.L., O'Toole, G.A. Infect. Immun. (2005) [Pubmed]
  20. Identification of sarV (SA2062), a new transcriptional regulator, is repressed by SarA and MgrA (SA0641) and involved in the regulation of autolysis in Staphylococcus aureus. Manna, A.C., Ingavale, S.S., Maloney, M., van Wamel, W., Cheung, A.L. J. Bacteriol. (2004) [Pubmed]
  21. {sigma}B Regulates IS256-Mediated Staphylococcus aureus Biofilm Phenotypic Variation. Valle, J., Vergara-Irigaray, M., Merino, N., Penadés, J.R., Lasa, I. J. Bacteriol. (2007) [Pubmed]
  22. SarS, a SarA homolog repressible by agr, is an activator of protein A synthesis in Staphylococcus aureus. Cheung, A.L., Schmidt, K., Bateman, B., Manna, A.C. Infect. Immun. (2001) [Pubmed]
  23. Impacts of sarA and agr in Staphylococcus aureus strain Newman on fibronectin-binding protein A gene expression and fibronectin adherence capacity in vitro and in experimental infective endocarditis. Xiong, Y.Q., Bayer, A.S., Yeaman, M.R., Van Wamel, W., Manna, A.C., Cheung, A.L. Infect. Immun. (2004) [Pubmed]
  24. sigma(B) activity in Staphylococcus aureus is controlled by RsbU and an additional factor(s) during bacterial growth. Palma, M., Cheung, A.L. Infect. Immun. (2001) [Pubmed]
  25. SarT, a repressor of alpha-hemolysin in Staphylococcus aureus. Schmidt, K.A., Manna, A.C., Gill, S., Cheung, A.L. Infect. Immun. (2001) [Pubmed]
  26. Role of SarA in virulence determinant production and environmental signal transduction in Staphylococcus aureus. Chan, P.F., Foster, S.J. J. Bacteriol. (1998) [Pubmed]
  27. SarA Is a Repressor of hla ({alpha}-Hemolysin) Transcription in Staphylococcus aureus: Its Apparent Role as an Activator of hla in the Prototype Strain NCTC 8325 Depends on Reduced Expression of sarS. Oscarsson, J., Kanth, A., Tegmark-Wisell, K., Arvidson, S. J. Bacteriol. (2006) [Pubmed]
  28. Coordinated and differential control of aureolysin (aur) and serine protease (sspA) transcription in Staphylococcus aureus by sarA, rot and agr (RNAIII). Oscarsson, J., Tegmark-Wisell, K., Arvidson, S. Int. J. Med. Microbiol. (2006) [Pubmed]
  29. Agr-independent regulation of fibronectin-binding protein(s) by the regulatory locus sar in Staphylococcus aureus. Wolz, C., Pöhlmann-Dietze, P., Steinhuber, A., Chien, Y.T., Manna, A., van Wamel, W., Cheung, A. Mol. Microbiol. (2000) [Pubmed]
  30. The two-component system ArlS-ArlR is a regulator of virulence gene expression in Staphylococcus aureus. Fournier, B., Klier, A., Rapoport, G. Mol. Microbiol. (2001) [Pubmed]
  31. SarA and not sigmaB is essential for biofilm development by Staphylococcus aureus. Valle, J., Toledo-Arana, A., Berasain, C., Ghigo, J.M., Amorena, B., Penadés, J.R., Lasa, I. Mol. Microbiol. (2003) [Pubmed]
  32. sar Genetic determinants necessary for transcription of RNAII and RNAIII in the agr locus of Staphylococcus aureus. Cheung, A.L., Bayer, M.G., Heinrichs, J.H. J. Bacteriol. (1997) [Pubmed]
 
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