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.[5][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.[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. 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.
  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. 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.
  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.
  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.
  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. doi:10.1073/pnas.1322033111. ISSN 1091-6490. PMC 4078829. PMID 24920590.
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