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An ability of pathogenic bacteria to survive in different ecological niches, to successfully adapt to changing environments, to colonize different organs and tissues, and to cause numerous diseases in human and animals including severe invasive diseases is provided, in particular, by the presence of specific proteins involved in regulation of gene transcription. This review summarizes the current data on the Rgg-family (TIGR01716 family, The Institute for Genomic Research, http://www.jcvi.org) of regulatory proteins encoded by some of the low G+C gram positive bacteria such as Streptococcus gordonii, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus mutans, Streptococcus thermophilus, Streptococcus suis and Streptococcus pyogenes. Proteins of this family has helix-turn-helix (HTH) motif at N-terminus which is able to bind promoter regions of the genes and regulate their transcription. The mechanisms of Rgg-dependent transcriptional regulation and the role of certain amino acids for functioning of Rgg-like proteins are discussed. The Rgg-like regulators have evolved to regulate diverse set of genes associated with virulence, metabolism, stress response, competence, biofilm formation, etc. The Rgg-like regulators are also involved in quorum sensing. Rgg-like proteins regulate not only the genes located adjacently to rgg, but also distantly located genes. Rgg-like proteins of different bacterial species have certain sequence similarity, and it is suggested that their genes are horizontally acquired. Rgg-dependent transcriptional regulation varies in a strainand species-specific manner that supports the hypothesis of the complexity of transcriptional regulation in gram-positive bacteria. The current review also discusses the role or Rgg-like regulators in control of virulent properties of gram-positive bacteria and their interaction with human host. Given the importance of Rgg-like regulators for virulence, these proteins (their genes or transcripts) can be considered as targets for development of the novel selective agents against different bacterial infections. 

About the authors

A. V. Dmitriev

Institute of Experimental Medicine, St. Petersburg, Russian Federation
St. Petersburg State Technological Institute (Technical University), St. Petersburg, Russian Federation

Author for correspondence.
Email: admitriev10@yandex.ru

PhD, MD (Biology), Deputy Director on Science, Head of the Department of Ecological Physiology, Institute
of Experimental Medicine; Professor of St. Petersburg State Technological Institute (Technical University)

Russian Federation

M. S. Chaussee

University of South Dakota, Vermillion, USA

Email: fake@neicon.ru

Professor, Division of Basic Biomedical Sciences, Stanford School of Medicine, University of South Dakota

Russian Federation

O. V. Kalinina

Almazov Northwest Federal Medical Research Center, St. Petersburg, Russian Federation
St. Petersburg Pasteur Institute, St. Petersburg, Russian Federation

Email: fake@neicon.ru

PhD, MD (Biology), Leading Researcher, Reseach Laboratory of Molecular Cardiology, Almazov Northwest Federal Medical Research Center; Leading Researcher, Laboratory of Molecular Microbiology, St. Petersburg Pasteur Institute

Russian Federation


  1. Дмитриев А.В. Регуляция транскрипции генов у стрептококков групп А и В // Медицинский академический журнал. 2010. T. 10, № 4. С. 256–266. [Dmitriev A.V. Regulation of gene transcription in group A and B streptococci. Meditsinskii akademicheskii zhurnal = Medical Academical Journal, 2010, vol. 10, no. 4, pp. 256–266. (In Russ.)]
  2. Дмитриев А.В., Chaussee M.S. Зависимость свойств Streptococcus pyogenes от уровня транскрипции гена rgg // Медицинский академический журнал. 2013. Т. 13, № 3. С. 114–119. [Dmitriev A.V., Chaussee M.S. Dependence of Streptococcus pyogenes properties from the rgg gene transcriptional level. Meditsinskii akademicheskii zhurnal = Medical Academical Journal, 2013, vol. 13, no. 3, pp. 114–119. (In Russ.)]
  3. Дмитриев А.В., Рождественская А.С., Зуткис А.А., Тотолян А.А. Направленная регуляция патогенных свойств стрептококков // Медицинский академический журнал. 2009. Т. 9, № 4. С. 50–58. [Dmitriev A.V., Rozhdestvenskaya A.S., Zutkis A.A., Totolian A.A. Targeted regulation of pathogenic properties in streptococci. Meditsinskii akademicheskii zhurnal = Medical Academical Journal, 2009, vol. 9, no. 4, pp. 50–58. (In Russ.)]
  4. Зуткис А.А., Мильман Б.Л., Дмитриев А.В. Роль гена mutR в метаболизме и вирулентности штаммов Streptococcus pyogenes генотипа emm12 // Инфекция и иммунитет. 2014, Т. 4, № 4. С. 339–346. [Zutkis A.A., Milman B.L., Dmitriev A.V. The role of mutR gene in metabolism and virulence of emm12 genotype Streptococcus pyogenes strains. Infektsiya i immunitet = Russian Journal of Infection and Immunity, 2014, vol. 4, no. 4, pp. 339–346. doi: 10.15789/2220-7619-2014-4-339-346 (In Russ.)]
  5. Рождественская А.С., Дмитриев А.В., Грабовская К.Б., Тотолян А.А. Инактивация гена регулятора транскрипции Rgg изменяет экспрессию секретируемых факторов патогенности и вирулентность Streptococcus pyogenes // Медицинский академический журнал. 2008. T. 8, № 2. C. 21–27. [Rozhdestvenskaya A.S., Dmitriyev A.V., Grabovskaya K.B., Totolian A.A. Inactivation of the transcription regulator gene Rgg leads to changes in the expression of secreted pathogenicity factors and the virulence of Streptococcus. Meditsinskii akademicheskii zhurnal = Medical Academical Journal, 2008, vol. 8, no. 2, pp. 21–27. (In Russ.)]
  6. Aggarwal C., Jimenez J.C., Nanavati D., Federle M.J. Multiple length peptide-pheromone variants produced by Streptococcus pyogenes directly bind Rgg proteins to confer transcriptional regulation. J. Biol. Chem., 2014, vol. 289, no. 32, pp. 22427–22436. doi: 10.1074/jbc.M114.583989
  7. Anbalagan S., Dmitriev A., McShan W.M., Dunman P.M., Chaussee M.S. Growth phase-dependent modulation of Rgg binding specificity in Streptococcus pyogenes. J. Bacteriol., 2012, vol. 194, no. 15, pp. 3961–3971. doi: 10.1128/JB.06709-11
  8. Anbalagan S., McShan W.M., Dunman P.M., Chaussee M.S. Identification of Rgg binding sites in the Streptococcus pyogenes chromosome. J. Bacteriol., 2011, vol. 193, no. 18, pp. 4933–4942. doi: 10.1128/JB.00429-11
  9. Anbalagan S., Chaussee M.S. Transcriptional regulation of a bacteriophage encoded extracellular DNase (Spd-3) by Rgg in Streptococcus pyogenes. PLoS One, 2013, vol. 8, no. 4:e61312. doi: 10.1371/journal.pone.0061312
  10. Balleza E., López-Bojorquez L.N., Martínez-Antonio A., Resendis-Antonio O., Lozada-Chávez I., Balderas-Martínez Y.I., Encarnación S., Collado-Vides J. Regulation by transcription factors in bacteria: beyond description. FEMS Microbiol. Rev., 2009, vol. 33, no. 1, pp. 133–151. doi: 10.1111/j.1574-6976.2008.00145.x
  11. Beres S., Sylva G.L., Barbian K.D., Lei B., Hoff J.S., Mammarella N.D., Liu M.Y., Smoot J.C., Porcella S.F., Parkins L.D., Campbell D.S., Smith T.M., McCormick J.K., Leung D.Y., Schlievert P.M., Musser J.M. Genome sequence of a serotype M3 strain of group A Streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc. Natl. Acad. Sci. USA, 2002, vol. 99, no. 15, pp. 10078–10083. doi: 10.1073/pnas.152298499
  12. Beres S.B., Carroll R.K., Shea P.R., Sitkiewicz I., Martinez-Gutierrez J.C., Low D.E., McGeer A., Willey B.M., Green K., Tyrrell G.J., Goldman T.D., Feldgarden M., Birren B.W., Fofanov Y., Boos J., Wheaton W.D., Honisch C., Musser J.M. Molecular complexity of successive bacterial epidemics deconvoluted by comparative pathogenomics. Proc. Natl. Acad. Sci. USA, 2010, vol. 107, no. 9, pp. 4371–4376. doi: 10.1073/pnas.0911295107
  13. Beres S.B., Richter E.W., Nagiec M.J., Sumby P., Porcella S.F., DeLeo F.R., Musser J.M. Molecular genetic anatomy of interand intraserotype variation in the human bacterial pathogen group A Streptococcus. Proc. Natl. Acad. Sci. USA, 2006, vol. 103, no. 18, pp. 7059–7064. doi: 10.1073/pnas.0510279103
  14. Bortoni M.E., Terra V.S., Hinds J., Andrew P.W., Yesilkaya H. The pneumococcal response to oxidative stress includes a role for Rgg. Microbiology, 2009, no. 155, pt. 12, pp. 4123–4134. doi: 10.1099/mic.0.028282-0
  15. Carroll R., Shelburne S.A. 3rd, Olsen R.J., Suber B., Sahasrabhojane P., Kumaraswami M., Beres S.B., Shea P.R., Flores A.R., Musser J.M. Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice. J. Clin. Invest., 2011, vol. 121, no. 5, pp. 1956–1968. doi: 10.1172/JCI45169
  16. Chang J.C., LaSarre B., Jimenez J.C., Aggarwal C., Federle M.J. Two group A streptococcal peptide pheromones act through opposing Rgg regulators to control biofilm development. PLoS Pathog., 2011, vol. 7, no. 8:e1002190. doi: 10.1371/journal.ppat.1002190
  17. Chaussee M.S., Watson R.O., Smoot J.C., Musser J.M. Identification of Rgg-regulated exoproteins of Streptococcus pyogenes. Infect. Immun., 2001, vol. 69, no. 2, pp. 822–831. doi: 10.1128/IAI.69.2.822-831.2001
  18. Chaussee M.S., Somerville G.A., Reitzer L., Musser J.M. Rgg coordinates virulence factor synthesis and metabolism in Streptococcus pyogenes. J. Bacteriol., 2003, vol. 185, no. 20, pp. 6016–6024. doi: 10.1128/JB.185.20.6016-6024.2003
  19. Chaussee M.S., Sylva G.L., Sturdevant D.E., Smoot L.M., Graham M.R., Watson R.O., Musser J.M. Rgg influences the expression of multiple regulatory loci to coregulate virulence factor expression in Streptococcus pyogenes. Infect. Immun., 2002, vol. 70, no. 2, pp. 762–770. doi: 10.1128/IAI.70.2.762-770.2002
  20. Chaussee M.A., Callegari E.A., Chaussee M.S. Rgg regulates growth phase-dependent expression of proteins associated with secondary metabolism and stress in Streptococcus pyogenes. J. Bacteriol., 2004, vol. 186, no. 21, pp. 7091–7099. doi: 10.1128/JB.186.21.7091-7099.2004
  21. Dmitriev A.V., McDowell E.J., Chaussee M.S. Interand intraserotypic variation in the Streptococcus pyogenes Rgg regulon. FEMS Microbiol. Lett., 2008, vol. 284, no. 1, pp. 43–51. doi: 10.1111/j.1574-6968.2008.01171.x
  22. Dmitriev A.V., McDowell E.J., Kappeler K.V., Chaussee M.A., Rieck L.D., Chaussee M.S. The Rgg regulator of Streptococcus pyogenes influences utilization of nonglucose carbohydrates, prophage induction, and expression of the NAD-glycohydrolase virulence operon. J. Bacteriol., 2006, vol. 188, no. 20, pp. 7230–7241. doi: 10.1128/JB.00877-06
  23. Engleberg N.C., Heath A., Miller A., Rivera C., DiRita V.J. Spontaneous mutations in the CsrRS two-component regulatory system of Streptococcus pyogenes result in enhanced virulence in a murine model of skin and soft tissue infection. J. Infect. Dis., 2001, vol. 183, no. 7, pp. 1043–1054. doi: 10.1086/319291
  24. Fernandez A., Thibessard A., Borges F., Gintz B., Decaris B., Leblond-Bourget N. Characterization of oxidative stress-resistant mutants of Streptococcus thermophilus CNRZ368. Arch. Microbiol., 2004, vol. 182, no. 5, pp. 364–372. doi: 10.1007/s00203-004-0712-2
  25. Fernandez A., Borges F., Gintz B., Decaris B., Leblond-Bourget N. The rggC locus, with a frameshift mutation, is involved in oxidative stress response by Streptococcus thermophilus. Arch. Microbiol, 2006, vol. 186, no. 3, pp. 161–169. doi: 10.1007/s00203-006-0130-8
  26. Fontaine L., Boutry C., de Frahan M.H., Delplace B., Fremaux C., Horvath P., Boyaval P., Hols P. A novel pheromone quorumsensing system controls the development of natural competence in Streptococcus thermophilus and Streptococcus salivarius. J. Bacteriol., 2010, vol. 192, no. 5, pp. 1444–1454. doi: 10.1128/JB.01251-09
  27. Fujiwara T., Hoshino T., Ooshima T., Sobue S., Hamada S. Purification, characterization, and molecular analysis of the gene encoding glucosyltransferase from Streptococcus oralis. Infect. Immun., 2000, vol. 68, no. 5, pp. 2475–2483. doi: 10.1128/IAI.68.5.2475-2483.2000
  28. Green N.M., Zhang S., Porcella S.F., Nagiec M.J., Barbian K.D., Beres S.B., LeFebvre R.B., Musser J.M. Genome sequence of a serotype M28 strain of group A streptococcus: potential new insights into puerperal sepsis and bacterial disease specificity. J. Infect. Dis., 2005, vol. 192, no. 5, pp. 760–770. doi: 10.1086/430618
  29. Herbert M.A., Beveridge C.J., McCormick D., Aten E., Jones N., Snyder L.A., Saunders N.J. Genetic islands of Streptococcus agalactiae strains NEM316 and 2603VR and their presence in other Group B streptococcal strains. BMC Microbiol., 2005, 5:31. doi: 10.1186/1471-2180-5-31
  30. Hollands A., Aziz R.K., Kansal R., Kotb M., Nizet V., Walker M.J. A naturally occurring mutation in ropB suppresses SpeB expression and reduces M1T1 group A streptococcal systemic virulence. PLoS One, 2008, vol. 3, no. 12, e4102. doi: 10.1371/journal.pone.0004102
  31. Hondorp E.R., McIver K.S. The Mga virulence regulon: infection where the grass is greener. Mol. Microbiol., 2007, vol. 66, no. 5, pp. 1056–1065. doi: 10.1111/j.1365-2958.2007.06006.x
  32. Ibrahim M., Nicolas P., Bessières P., Bolotin A., Monnet V., Gardan R. A genome-wide survey of short coding sequences in streptococci. Microbiology, 2007, vol. 153, pt. 11, pp. 3631–3644. doi: 10.1099/mic.0.2007/006205-0
  33. Ikebe T., Ato M., Matsumura T., Hasegawa H., Sata T., Kobayashi K., Watanabe H. Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates. PLoS Pathog., 2010, vol. 6, no. 4, e1000832. doi: 10.1371/journal.ppat.1000832
  34. Kappeler K.V., Anbalagan S., Dmitriev A.V., McDowell E.J., Neely M.N., Chaussee M.S. A naturally occurring Rgg variant in serotype M3 Streptococcus pyogenes does not activate speB expression due to altered specificity of DNA binding. Infect. Immun., 2009, vol. 77, no. 12, pp. 5411–5417. doi: 10.1128/IAI.00373-09
  35. Loughman J.A., Caparon M.G. A novel adaptation of aldolase regulates virulence in Streptococcus pyogenes. Embo J., 2006, vol. 25, no. 22, pp. 5414–5422. doi: 10.1038/sj.emboj.7601393
  36. Loughman J.A., Caparon M.G. Contribution of invariant residues to the function of Rgg family transcription regulators. J. Bacteriol., 2007, vol. 189, no. 2, pp. 650–655. doi: 10.1128/JB.01437-06
  37. Loughman J.A., Caparon M. Regulation of SpeB in Streptococcus pyogenes by pH and NaCl: a model for in vivo gene expression. J. Bacteriol., 2006, vol. 188, no. 2, pp. 399–408. doi: 10.1128/JB.188.2.399-408.2006
  38. Lyon W., Gibson C.M., Caparon M.G. A role for trigger factor and an rgg-like regulator in the transcription, secretion and processing of the cysteine proteinase of Streptococcus pyogenes. EMBO J., 1998, vol. 17, no. 21, pp. 6263–6275. doi: 10.1093/emboj/17.21.6263
  39. Merritt J., Kreth J., Shi W., Qi F. LuxS controls bacteriocin production in Streptococcus mutans through a novel regulatory component. Mol. Microbiol., 2005, vol. 57, no. 4, pp. 960–969. doi: 10.1111/j.1365-2958.2005.04733.x
  40. Nakagawa I., Kurokawa K., Yamashita A., Nakata M., Tomiyasu Y., Okahashi N., Kawabata S., Yamazaki K., Shiba T., Yasunaga T., Hayashi H., Hattori M., Hamada S. Genome sequence of an M3 strain of Streptococcus pyogenes reveals a largescale genomic rearrangement in invasive strains and new insights into phage evolution. Genome Res., 2003, vol. 13, pp. 1042–1055. doi: 10.1101/gr.1096703
  41. Parashar V., Aggarwal C., Federle M.J., Neiditch M.B. Rgg protein structure-function and inhibition by cyclic peptide compounds. Proc. Natl. Acad. Sci. USA, 2015, vol. 112, no. 16, pp. 5177–5182. doi: 10.1073/pnas.1500357112
  42. Paterson G.K., Blue C.E., Mitchell T.J. Role of two-component systems in the virulence of Streptococcus pneumoniae. J. Med. Microbiol., 2006, vol. 55, pt. 4, pp. 355–363.
  43. Pérez-Pascual D., Gaudu P., Fleuchot B., Besset C., Rosinski-Chupin I., Guillot A., Monnet V., Gardan R. RovS and its associated signaling peptide form a cell-to-cell communication system required for Streptococcus agalactiae pathogenesis. MBio, 2015, vol. 6, no. 1, e02306-14. doi: 10.1128/mBio.02306-14
  44. Pulliainen A.T., Hytönen J., Haataja S., Finne J. Deficiency of the Rgg regulator promotes H2O2 resistance, AhpCF-mediated H2O2 decomposition, and virulence in Streptococcus pyogenes. J. Bacteriol., 2008, vol. 190, no. 9, pp. 3225–3235. doi: 10.1128/JB.01843-07
  45. Qi F., Chen P., Caufield P.W. Purification of mutacin III from group III Streptococcus mutans UA787 and genetic analyses of mutacin III biosynthesis genes. Appl. Environ. Microbiol., 1999, vol. 65, no. 9, pp. 3880–3887.
  46. Rawlinson E.L., Nes I.F., Skaugen M. Identification of the DNA-binding site of the Rgg-like regulator LasX within the lactocin S promoter region. Microbiology, 2005, vol. 151, pt. 3, pp. 813–823. doi: 10.1099/mic.0.27364-0
  47. Sanders J.W., Leenhouts K., Burghoorn J., Brands J.R., Venema G., Kok J. A chloride-inducible acid resistance mechanism in Lactococcus lactis and its regulation. Mol. Microbiol., 1998, vol. 27, no. 2, pp. 299–310. doi: 10.1046/j.1365-2958.1998.00676.x
  48. Samen U.M., Eikmanns B.J., Reinscheid D.J. The transcriptional regulator RovS controls the attachment of Streptococcus agalactiae to human epithelial cells and the expression of virulence genes. Infect. Immun., 2006, vol. 74, no. 10, pp. 5625–5635. doi: 10.1128/IAI.00667-06
  49. Smoot J., Barbian K.D., Van Gompel J.J., Smoot L.M., Chaussee M.S., Sylva G.L., Sturdevant D.E., Ricklefs S.M., Porcella S.F., Parkins L.D., Beres S.B., Campbell D.S., Smith T.M., Zhang Q., Kapur V., Daly J.A., Veasy L.G., Musser J.M. Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks. Proc. Natl. Acad. Sci. USA, 2002, vol. 99, no. 7, pp. 4668–4673. doi: 10.1073/pnas.062526099
  50. Tettelin H., Masignani V., Cieslewicz M.J., Donati C., Medini D., Ward N.L., Angiuoli S.V., Crabtree J., Jones A.L., Durkin A.S., Deboy R.T., Davidsen T.M., Mora M., Scarselli M., Margarit. y Ros. I., Peterson J.D., Hauser C.R., Sundaram J.P., Nelson W.C., Madupu R., Brinkac L.M., Dodson R.J., Rosovitz M.J., Sullivan S.A., Daugherty S.C., Haft D.H., Selengut J., Gwinn M.L., Zhou L., Zafar N., Khouri H., Radune D., Dimitrov G., Watkins K., O’Connor K.J., Smith S., Utterback T.R., White O., Rubens C.E., Grandi G., Madoff L.C., Kasper D.L., Telford J.L., Wessels M.R., Rappuoli R., Fraser C.M. Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: implications for the microbial “pan-genome”. Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 39, pp. 13950–13955. doi: 10.1073/pnas.0506758102
  51. Vahling C.M., McIver K.S. Identification of residues responsible for the defective virulence gene regulator Mga produced by a natural mutant of Streptococcus pyogenes. J. Bacteriol., 2005, vol. 187, no. 17, pp. 5955–5966. doi: 10.1128/JB.187.17.5955-5966.2005
  52. Vickerman M.M., Wang M., Baker L.J. An amino acid change near the carboxyl terminus of the Streptococcus gordonii regulatory protein Rgg affects its abilities to bind DNA and influence expression of the glucosyltransferase gene gtfG. Microbiology, 2003, vol. 149, pt. 2, pp. 399–406. doi: 10.1099/mic.0.25983-0
  53. Vickerman M.M., Minick P.E., Mather N.M. Characterization of the Streptococcus gordonii chromosomal region immediately downstream of the glucosyltransferase gene. Microbiology, 2001, vol. 147, iss. 11, pp. 3061–3070. doi: 10.1099/00221287-147-11-3061
  54. Vickerman M.M., Minick P.E. Genetic analysis of the rgg-gtfG junctional region and its role in Streptococcus gordonii glucosyltransferase activity. Infect. Immun., 2002, vol. 70, no. 4, pp. 1703–1714. doi: 10.1128/IAI.70.4.1703-1714.2002
  55. Vickerman M.M., Iobst S., Jesionowski A.M., Gill S.R. Genome-wide transcriptional changes in Streptococcus gordonii in response to competence signaling peptide. J. Bacteriol., 2007, vol. 189, no. 21, pp. 7799–7807. doi: 10.1128/JB.01023-07
  56. Xu P., Alves J.M., Kitten T., Brown A., Chen Z., Ozaki L.S., Manque P., Ge X., Serrano M.G., Puiu D., Hendricks S., Wang Y., Chaplin M.D., Akan D., Paik S., Peterson D.L., Macrina F.L., Buck G.A. Genome of the opportunistic pathogen Streptococcus sanguinis. J. Bacteriol., 2007, vol. 189, no. 8, pp. 3166–3175. doi: 10.1128/JB.01808-06
  57. Zheng F., Ji H., Cao M., Wang C., Feng Y., Li M., Pan X., Wang J., Qin Y., Hu F., Tang J. Contribution of the Rgg transcription regulator to metabolism and virulence of Streptococcus suis serotype 2. Infect. Immun., 2011, vol. 79, no. 3, pp. 1319–1328. doi: 10.1128/IAI.00193-10
  58. Zutkis A.A., Anbalagan S., Chaussee M.S., Dmitriev A.V. Inactivation of the Rgg2 transcriptional regulator ablates the virulence of Streptococcus pyogenes. PLoS One, 2014, vol. 9, no. 12, e114784. doi: 10.1371/journal.pone.0114784

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