Locus of enterocyte effacement-encoded regulator explained

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.

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] __TOC__

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] 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.[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. 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.

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. 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]

Notes and References

  1. Mellies. J. L.. Elliott. S. J.. Sperandio. V.. Donnenberg. M. S.. Kaper. J. B.. July 1999. 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. 296–306. 0950-382X. 10411746. 10.1046/j.1365-2958.1999.01473.x. 23881901.
  2. Bustamante. V. H.. Santana. F. J.. Calva. E.. Puente. J. L.. February 2001. Transcriptional regulation of type III secretion genes in enteropathogenic Escherichia coli: Ler antagonizes H-NS-dependent repression. Molecular Microbiology. 39. 3. 664–678. 0950-382X. 11169107. 10.1046/j.1365-2958.2001.02209.x. free.
  3. Sircili. Marcelo P.. Walters. Matthew. Trabulsi. Luis R.. Sperandio. Vanessa. 2004-04-01. Modulation of Enteropathogenic Escherichia coli Virulence by Quorum Sensing. Infection and Immunity. en. 72. 4. 2329–2337. 10.1128/iai.72.4.2329-2337.2004. 0019-9567. 15039358. 375187.
  4. Barba. Jeannette. Bustamante. Víctor H.. Flores-Valdez. Mario A.. Deng. Wanyin. Finlay. B. Brett. Puente. José L.. 2005-12-01. A Positive Regulatory Loop Controls Expression of the Locus of Enterocyte Effacement-Encoded Regulators Ler and GrlA. Journal of Bacteriology. en. 187. 23. 7918–7930. 10.1128/jb.187.23.7918-7930.2005. 0021-9193. 16291665. 1291265.
  5. Winardhi. Ricksen S.. Gulvady. Ranjit. Mellies. Jay L.. Yan. Jie. 2014-05-16. Locus of enterocyte effacement-encoded regulator (Ler) of pathogenic Escherichia coli competes off histone-like nucleoid-structuring protein (H-NS) through noncooperative DNA binding. The Journal of Biological Chemistry. 289. 20. 13739–13750. 10.1074/jbc.M113.545954. 1083-351X. 4022848. 24668810. free.
  6. Lim. Ci Ji. Lee. Sin Yi. Kenney. Linda J.. Yan. Jie. 2012. Nucleoprotein filament formation is the structural basis for bacterial protein H-NS gene silencing. Scientific Reports. 2. 509. 10.1038/srep00509. 2045-2322. 3396134. 22798986. 2012NatSR...2E.509L.
  7. Mellies. Jay L.. Benison. Gregory. McNitt. William. Mavor. David. Boniface. Chris. Larabee. Frederick J.. April 2011. Ler of pathogenic Escherichia coli forms toroidal protein-DNA complexes. Microbiology. 157. Pt 4. 1123–1133. 10.1099/mic.0.046094-0. free . 1465-2080. 3139439. 21212119.
  8. Friedberg. Devorah. Umanski. Tatiana. Fang. Yuan. Rosenshine. Ilan. 1999-12-01. Hierarchy in the expression of the locus of enterocyte effacement genes of enteropathogenic Escherichia coli. Molecular Microbiology. en. 34. 5. 941–952. 10.1046/j.1365-2958.1999.01655.x. 10594820. 1365-2958. free.
  9. Goldberg. M. D.. Johnson. M.. Hinton. J. C. D.. Williams. P. H.. 2001-08-01. Role of the nucleoid-associated protein Fis in the regulation of virulence properties of enteropathogenic Escherichia coli. Molecular Microbiology. en. 41. 3. 549–559. 10.1046/j.1365-2958.2001.02526.x. 11532124. 1365-2958.
  10. Grant. Andrew J.. Farris. Michele. Alefounder. Peter. Williams. Peter H.. Woodward. Martin J.. O'Connor. C. David. 2003-04-01. Co-ordination of pathogenicity island expression by the BipA GTPase in enteropathogenic Escherichia coli (EPEC). Molecular Microbiology. en. 48. 2. 507–521. 10.1046/j.1365-2958.2003.t01-1-03447.x. 12675808. 1365-2958. free.
  11. Berdichevsky. Tatiana. Friedberg. Devorah. Nadler. Chen. Rokney. Assaf. Oppenheim. Amos. Rosenshine. Ilan. 2005-01-01. Ler Is a Negative Autoregulator of the LEE1 Operon in Enteropathogenic Escherichia coli. Journal of Bacteriology. en. 187. 1. 349–357. 10.1128/jb.187.1.349-357.2005. 0021-9193. 15601719. 538822.
  12. Bhat. Abhayprasad. Shin. Minsang. Jeong. Jae-Ho. Kim. Hyun-Ju. Lim. Hyung-Ju. Rhee. Joon Haeng. Paik. Soon-Young. Takeyasu. Kunio. Tobe. Toru. 2014-06-24. DNA looping-dependent autorepression of LEE1 P1 promoters by Ler in enteropathogenic Escherichia coli (EPEC). Proceedings of the National Academy of Sciences of the United States of America. 111. 25. E2586–2595. 10.1073/pnas.1322033111. 1091-6490. 4078829. 24920590. 2014PNAS..111E2586B. free.

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