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Locus of enterocyte effacement-encoded regulator

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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). 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. 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. 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.

Mechanism

Ler positively regulates the LEE genes by competition with its homolog, H-NS. H-NS silences LEE genes via rigid filament structures bound to the DNA that Ler disrupts and replaces through unknown mechanisms. 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.

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.

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. BipA, a ribosomal binding GTPase and prolific regulator of EPEC virulence, transcriptionally regulates Ler from an upstream position where it also regulates other genes.

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

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. doi:10.1046/j.1365-2958.1999.01473.x. ISSN 0950-382X. PMID 10411746. S2CID 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. doi:10.1046/j.1365-2958.2001.02209.x. ISSN 0950-382X. PMID 11169107.
  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. 72 (4): 2329–2337. doi:10.1128/iai.72.4.2329-2337.2004. ISSN 0019-9567. PMC 375187. PMID 15039358.
  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. 187 (23): 7918–7930. doi:10.1128/jb.187.23.7918-7930.2005. ISSN 0021-9193. PMC 1291265. PMID 16291665.
  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. doi:10.1074/jbc.M113.545954. ISSN 1083-351X. PMC 4022848. PMID 24668810.
  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. Bibcode:2012NatSR...2E.509L. doi:10.1038/srep00509. ISSN 2045-2322. PMC 3396134. PMID 22798986.
  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. doi:10.1099/mic.0.046094-0. ISSN 1465-2080. PMC 3139439. PMID 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. 34 (5): 941–952. doi:10.1046/j.1365-2958.1999.01655.x. ISSN 1365-2958. PMID 10594820.
  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. 41 (3): 549–559. doi:10.1046/j.1365-2958.2001.02526.x. ISSN 1365-2958. PMID 11532124.
  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. 48 (2): 507–521. doi:10.1046/j.1365-2958.2003.t01-1-03447.x. ISSN 1365-2958. PMID 12675808.
  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. 187 (1): 349–357. doi:10.1128/jb.187.1.349-357.2005. ISSN 0021-9193. PMC 538822. PMID 15601719.
  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. Bibcode:2014PNAS..111E2586B. doi:10.1073/pnas.1322033111. ISSN 1091-6490. PMC 4078829. PMID 24920590.
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