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Mutational analysis of the locus of enterocyte effacement-encoded regulator (Ler) of enteropathogenic Escherichia coli.

ABSTRACT: The locus of enterocyte effacement (LEE) pathogenicity island of enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC, respectively) comprises a cluster of operons encoding a type III secretion system and related proteins, all of which are essential for bacterial colonization of the host intestines. The LEE1 operon encodes Ler, which positively regulates many EPEC and EHEC virulence genes located in the LEE region and elsewhere in the chromosome. In addition, Ler is a specific autorepressor of LEE1 transcription. To better understand the function of Ler, we screened for Ler mutants defective in autorepression. We isolated 18 different point mutations in Ler, rendering it defective in autorepression and in DNA binding. Among these mutants were those defective in positive regulation as well as in autorepression, dominant-negative mutants, and a mutant deficient in oligomerization. Importantly, a group of Ler autorepression mutants complemented an EPEC ler deletion mutant for transcription activation in a dosage-dependent manner, suggesting that Ler and possibly other autorepressors have an intrinsic compensatory mechanism that enables them to sustain mutations. In addition, the phenotypes of the different mutants identified by the screen define a novel domain in Ler that is required for oligomerization.

SUBMITTER: Yerushalmi G

PROVIDER: S-EPMC2583616 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Mutational analysis of the locus of enterocyte effacement-encoded regulator (Ler) of enteropathogenic Escherichia coli.

Yerushalmi Gal G Nadler Chen C Berdichevski Tatiana T Rosenshine Ilan I

Journal of bacteriology 20081003 23

The locus of enterocyte effacement (LEE) pathogenicity island of enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC, respectively) comprises a cluster of operons encoding a type III secretion system and related proteins, all of which are essential for bacterial colonization of the host intestines. The LEE1 operon encodes Ler, which positively regulates many EPEC and EHEC virulence genes located in the LEE region and elsewhere in the chromosome. In addition, Ler is a specific ...[more]

PMID: 18835988

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Project description:In enteropathogenic Escherichia coli (EPEC), the locus of enterocyte effacement (LEE) encodes a type 3 secretion system (T3SS) essential for pathogenesis. This pathogenicity island comprises five major operons (LEE1 to LEE5), with the LEE5 operon encoding T3SS effectors involved in the intimate adherence of bacteria to enterocytes. The first operon, LEE1, encodes Ler (LEE-encoded regulator), an H-NS (nucleoid structuring protein) paralog that alleviates the LEE H-NS silencing. We observed that the LEE5 and LEE1 promoters present a bimodal expression pattern, depending on environmental stimuli. One key regulator of bimodal LEE1 and LEE5 expression is ler expression, which fluctuates in response to different growth conditions. Under conditions in vitro considered to be equivalent to nonoptimal conditions for virulence, the opposing regulatory effects of H-NS and Ler can lead to the emergence of two bacterial subpopulations. H-NS and Ler share nucleation binding sites in the LEE5 promoter region, but H-NS binding results in local DNA structural modifications distinct from those generated through Ler binding, at least in vitro Thus, we show how two nucleoid-binding proteins can contribute to the epigenetic regulation of bacterial virulence and lead to opposing bacterial fates. This finding implicates for the first time bacterial-chromatin structural proteins in the bimodal regulation of gene expression.IMPORTANCE Gene expression stochasticity is an emerging phenomenon in microbiology. In certain contexts, gene expression stochasticity can shape bacterial epigenetic regulation. In enteropathogenic Escherichia coli (EPEC), the interplay between H-NS (a nucleoid structuring protein) and Ler (an H-NS paralog) is required for bimodal LEE5 and LEE1 expression, leading to the emergence of two bacterial subpopulations (with low and high states of expression). The two proteins share mutual nucleation binding sites in the LEE5 promoter region. In vitro, the binding of H-NS to the LEE5 promoter results in local structural modifications of DNA distinct from those generated through Ler binding. Furthermore, ler expression is a key parameter modulating the variability of the proportions of bacterial subpopulations. Accordingly, modulating the production of Ler into a nonpathogenic E. coli strain reproduces the bimodal expression of LEE5 Finally, this study illustrates how two nucleoid-binding proteins can reshape the epigenetic regulation of bacterial virulence.

Dataset Information

Mutational analysis of the locus of enterocyte effacement-encoded regulator (Ler) of enteropathogenic Escherichia coli.

Publications

Mutational analysis of the locus of enterocyte effacement-encoded regulator (Ler) of enteropathogenic Escherichia coli.

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