Accessory gene regulator explained

Accessory gene regulator (agr) is a complex 5 gene locus that is a global regulator of virulence in Staphylococcus aureus.[1] [2] [3] It encodes a two-component transcriptional quorum-sensing (QS) system activated by an autoinducing, thiolactone-containing cyclic peptide (AIP).[4]

Agr occurs in 4 allelic subtypes that have an important role in staphylococcal evolution.[5] [6] The corresponding AIPs are mutually cross-inhibitory, which may enhance the evolutionary separation of the 4 groups.[7] The agr receptor, AgrC, is a model histidine phosphokinase (HPK) that has been used to decipher the molecular mechanism of signal transduction.[8] AIP binding to the extracellular domain of AgrC causes twisting of the intracellular a-helical domain so as to enable trans-phosphorylation of the active site histidine;  the inhibitory AIPs cause the α-helical domain to twist in the opposite direction, preventing trans-phosphorylation. The agr QS circuit autoactivates transcription of agrA which, in turn upregulates the phenol-souble modulins.[9] More importantly, it activates transcription of a divergently oriented promoter whose transcript, known as RNAIII,[10] is a 514 nt regulatory RNA that encodes δ-hemolysin and is the major effector of the agr regulon. RNAIII acts by antisense inhibition or activation of target gene translation. In vitro, early in growth, genes encoding surface proteins important for adhesion and immune evasion (such as spa – encoding proteinA[11]) are expressed, enabling the organism to gain a foothold. Later in growth, these genes are down-regulated by RNAIII and those encoding toxins, hemolysins and other virulence-related proteins, are turned on, enabling the organism to establish and promulgate its pathological programs, such as abscess formation.[12] It is assumed that this program operates in vivo as well. As agr is essential for staphylococcal contagion,[13] agr-defective mutants are not contagious, but enable the organism's long-term survival in chronic conditions such as surgical implant infections, osteomyelitis or the infected lung in cystic fibrosis. In keeping with this behavior, mutations inactivating agr function enhance the stability of biofilms,[14] which are key to the maintenance of chronic infections.

Agr is widely conserved among Bacillota[15] and has a well-defined role in virulence regulation in several genera, especially Listeria and Clostridia.

Notes and References

  1. Recsei P, Kreiswirth B, O'Reilly M, Schlievert P, Gruss A, Novick RP . Regulation of exoprotein gene expression in Staphylococcus aureus by agar . Molecular & General Genetics . 202 . 1 . 58–61 . January 1986 . 3007938 . 10.1007/BF00330517 . 8592594 .
  2. Gomes-Fernandes M, Laabei M, Pagan N, Hidalgo J, Molinos S, Villar Hernandez R, Domínguez-Villanueva D, Jenkins AT, Lacoma A, Prat C . 6 . Accessory gene regulator (Agr) functionality in Staphylococcus aureus derived from lower respiratory tract infections . PLOS ONE . 12 . 4 . e0175552 . 2017-04-14 . 28410390 . 5391941 . 10.1371/journal.pone.0175552 . 2017PLoSO..1275552G . free .
  3. Tan L, Li SR, Jiang B, Hu XM, Li S . Therapeutic Targeting of the Staphylococcus aureus Accessory Gene Regulator (agr) System . Frontiers in Microbiology . 9 . 55 . 2018 . 29422887 . 5789755 . 10.3389/fmicb.2018.00055 . free .
  4. Ji G, Beavis RC, Novick RP . Cell density control of staphylococcal virulence mediated by an octapeptide pheromone . Proceedings of the National Academy of Sciences of the United States of America . 92 . 26 . 12055–9 . December 1995 . 8618843 . 40295 . 10.1073/pnas.92.26.12055 . 1995PNAS...9212055J . free .
  5. Wright JS, Traber KE, Corrigan R, Benson SA, Musser JM, Novick RP . The agr radiation: an early event in the evolution of staphylococci . Journal of Bacteriology . 187 . 16 . 5585–94 . August 2005 . 16077103 . 1196086 . 10.1128/JB.187.16.5585-5594.2005 .
  6. Jarraud S, Lyon GJ, Figueiredo AM, Lina G, Gérard L, Vandenesch F, Etienne J, Muir TW, Novick RP . 6 . Exfoliatin-producing strains define a fourth agr specificity group in Staphylococcus aureus . Journal of Bacteriology . 182 . 22 . 6517–22 . November 2000 . 11053400 . 94802 . 10.1128/jb.182.22.6517-6522.2000 .
  7. Ji G, Beavis R, Novick RP . Bacterial interference caused by autoinducing peptide variants . Science . 276 . 5321 . 2027–30 . June 1997 . 9197262 . 10.1126/science.276.5321.2027 .
  8. Wang B, Zhao A, Xie Q, Olinares PD, Chait BT, Novick RP, Muir TW . Functional Plasticity of the AgrC Receptor Histidine Kinase Required for Staphylococcal Virulence . Cell Chemical Biology . 24 . 1 . 76–86 . January 2017 . 28065658 . 5697745 . 10.1016/j.chembiol.2016.12.008 .
  9. Chatterjee SS, Chen L, Joo HS, Cheung GY, Kreiswirth BN, Otto M . Distribution and regulation of the mobile genetic element-encoded phenol-soluble modulin PSM-mec in methicillin-resistant Staphylococcus aureus . PLOS ONE . 6 . 12 . e28781 . 2011-12-12 . 22174895 . 3236207 . 10.1371/journal.pone.0028781 . 2011PLoSO...628781C . Horsburgh MJ . free .
  10. Novick RP, Ross HF, Projan SJ, Kornblum J, Kreiswirth B, Moghazeh S . Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule . The EMBO Journal . 12 . 10 . 3967–75 . October 1993 . 7691599 . 10.1002/j.1460-2075.1993.tb06074.x . 413679 .
  11. Benito Y, Kolb FA, Romby P, Lina G, Etienne J, Vandenesch F . Probing the structure of RNAIII, the Staphylococcus aureus agr regulatory RNA, and identification of the RNA domain involved in repression of protein A expression . RNA . 6 . 5 . 668–79 . May 2000 . 10836788 . 1369947 . 10.1017/S1355838200992550 .
  12. Novick RP . Autoinduction and signal transduction in the regulation of staphylococcal virulence . Molecular Microbiology . 48 . 6 . 1429–49 . June 2003 . 12791129 . 10.1046/j.1365-2958.2003.03526.x . 6847208 . free .
  13. Shopsin B, Eaton C, Wasserman GA, Mathema B, Adhikari RP, Agolory S, Altman DR, Holzman RS, Kreiswirth BN, Novick RP . 6 . Mutations in agr do not persist in natural populations of methicillin-resistant Staphylococcus aureus . The Journal of Infectious Diseases . 202 . 10 . 1593–9 . November 2010 . 20942648 . 10.1086/656915 . free .
  14. Kong KF, Vuong C, Otto M . Staphylococcus quorum sensing in biofilm formation and infection . International Journal of Medical Microbiology . 296 . 2–3 . 133–9 . April 2006 . 16487744 . 10.1016/j.ijmm.2006.01.042 .
  15. Wuster A, Babu MM . Conservation and evolutionary dynamics of the agr cell-to-cell communication system across firmicutes . Journal of Bacteriology . 190 . 2 . 743–6 . January 2008 . 17933897 . 2223712 . 10.1128/JB.01135-07 .

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