Locus of enterocyte effacement-encoded regulator

The locus of enterocyte effacement-encoded regulator (Ler) is a regulatory protein that controls bacterial pathogenicity of enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC).[1] More specifically, Ler regulates the locus of enterocyte effacement (LEE) pathogenicity island genes, which are responsible for creating intestinal attachment and effacing lesions and subsequent diarrhea: LEE1, LEE2, and LEE3.[1] LEE1, 2, and 3 carry the information necessary for a type III secretion system. The transcript encoding the Ler protein is the open reading frame 1 on the LEE1 operon.[1]

The mechanism of Ler regulation involves competition with histone-like nucleoid structuring protein (H-NS), a negative regulator of the LEE pathogenicity island.[2] Ler is regulated by many factors such as plasmid encoded regulator (Per), integration host factor, Fis, BipA, a positive regulatory loop involving GrlA, and quorum sensing mediated by luxS.[3][4]

Mechanism

Ler positively regulates the LEE genes by competition with its homolog, H-NS.[5] H-NS silences LEE genes via rigid filament structures bound to the DNA that Ler disrupts and replaces through unknown mechanisms.[6][5] Though little is known of the mechanism of Ler regulation, Ler interacts with DNA in specific ways. Ler binds DNA non-cooperatively, bends DNA in low concentrations, stiffens it in high concentration, and forms toroidal nucleoprotein complexes along DNA in vivo.[5][7]

Regulation

The regulation of Ler and its transcript, ler, is complex and many-fold. The plasmid encoded regulator (per) directly activates the region of the LEE1 operon which encodes Ler.[1] Integration host factor is also a direct activator of ler and binds upstream of its promoter.[8]

Jeannette Barba and her colleagues at the National Autonomous University of Mexico elucidated a positive regulatory loop between Ler, ler, GrlA, and grlRA. GrlA is also a LEE encoded regulator of the LEE pathogenicity island. They found that GrlA activates ler, and that Ler activates grlRA indicating a loop of activation wherein a protein product activates a transcript whose protein product activates the transcript of the original protein. Ler activates grlRA only if H-NS is present, this is not the case for GrlA activation of ler.[4]

Quorum sensing plays a role in Ler regulation. LuxS is an important protein involved in quorum sensing, particularly in the synthesis of autoinducer molecules. Quorum-sensing E. coli regulator A (QseA) is found in LuxS systems and activates transcription of ler.[3] Fis, a nucleoid associated protein essential for EPEC’s ability to form attaching and effacing lesions, partly acts through activation of Ler expression.[9] BipA, a ribosomal binding GTPase and prolific regulator of EPEC virulence, transcriptionally regulates Ler from an upstream position where it also regulates other genes.[10]

The Ler protein also represses its own transcript on the LEE1 operon through DNA looping which prevents RNA polymerase from completing transcription.[11][12]

References

  1. 1 2 3 4 Mellies, Jay L., et al. "The Per regulon of enteropathogenic Escherichia coli: identification of a regulatory cascade and a novel transcriptional activator, the locus of enterocyte effacement (LEE)‐encoded regulator (Ler)." Molecular microbiology 33.2 (1999): 296-306.
  2. ↑ Bustamante, V., Santana, F. J., Calva, E., & Puente, J. L. (2001). Transcriptional regulation of type III secretion genes in enteropathogenic Escherichia coli: Ler antagonizes H‐NS‐dependent repression. Molecular microbiology, 39(3), 664-678.
  3. 1 2 Sircili, M. P., Walters, M., Trabulsi, L. R., & Sperandio, V. (2004). Modulation of enteropathogenic Escherichia coli virulence by quorum sensing. Infection and immunity, 72(4), 2329-2337.
  4. 1 2 Barba, J., Bustamante, V. H., Flores-Valdez, M. A., Deng, W., Finlay, B. B., & Puente, J. L. (2005). A positive regulatory loop controls expression of the locus of enterocyte effacement-encoded regulators Ler and GrlA. Journal of Bacteriology, 187(23), 7918-7930.
  5. 1 2 3 Winardhi, Ricksen S., et al. "Locus of enterocyte effacement-encoded regulator (Ler) of pathogenic Escherichia coli competes off histone-like nucleoid-structuring protein (H-NS) through non-cooperative DNA binding." Journal of Biological Chemistry 289.20 (2014): 13739-13750.
  6. ↑ Lim, C. J., Lee, S. Y., Kenney, L. J., and Yan, J. (2012) Nucleoprotein filament formation is the structural basis for bacterial protein H-NS gene silencing. Sci Rep 2, 509
  7. ↑ Mellies, Jay L., et al. "Ler of pathogenic Escherichia coli forms toroidal protein–DNA complexes." Microbiology 157.4 (2011): 1123-1133.
  8. ↑ Friedberg, D., Umanski, T., Fang, Y. and Rosenshine, I. (1999), Hierarchy in the expression of the locus of enterocyte effacement genes of enteropathogenic Escherichia coli. Molecular Microbiology, 34: 941–952. doi:10.1046/j.1365-2958.1999.01655.x
  9. ↑ Goldberg, M. D., Johnson, M., Hinton, J. C. D. and Williams, P. H. (2001), Role of the nucleoid-associated protein Fis in the regulation of virulence properties of enteropathogenic Escherichia coli. Molecular Microbiology, 41: 549–559. doi:10.1046/j.1365-2958.2001.02526.x
  10. ↑ Grant, A. J., Farris, M., Alefounder, P., Williams, P. H., Woodward, M. J. and O'Connor, C. D. (2003), Co-ordination of pathogenicity island expression by the BipA GTPase in enteropathogenic Escherichia coli (EPEC). Molecular Microbiology, 48: 507–521. doi:10.1046/j.1365-2958.2003.t01-1-03447.x
  11. ↑ Berdichevsky, T., Friedberg, D., Nadler, C., Rokney, A., Oppenheim, A., & Rosenshine, I. (2005). Ler is a negative autoregulator of the LEE1 operon in enteropathogenic Escherichia coli. Journal of Bacteriology, 187(1), 349-357.
  12. ↑ Bhat, A., Shin, M., Jeong, J. H., Kim, H. J., Lim, H. J., Rhee, J. H., ... & Lee, G. (2014). DNA looping-dependent autorepression of LEE1 P1 promoters by Ler in enteropathogenic Escherichia coli (EPEC). Proceedings of the National Academy of Sciences, 111(25), E2586-E2595
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