Regine Hengge

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany

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Publications (53)325.22 Total impact

  • Tatyana L Povolotsky · Regine Hengge
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    ABSTRACT: The ubiquitous bacterial second messenger c-di-GMP has recently become prominent as a trigger for biofilm formation in many bacteria. It is generated by diguanylate cyclases (DGC, with GGDEF domains) and degraded by specific phosphodiesterases (PDE, containing either EAL or HD-GYP domains). Most bacterial species contain multiples of these proteins with some having specific functions that are based on direct molecular interactions in addition to their enzymatic activities. E. coli K-12 laboratory strains feature 29 genes encoding GGDEF and/or EAL domains, resulting in a set of 12 DGCs, 13 PDEs and four enzymatically inactive 'degenerate' proteins that act by direct macromolecular interactions. Here we present a comparative analysis of GGDEF/EAL domain-encoding genes in 61 genomes of pathogenic, commensal and probiotic E. coli strains (including enteric pathogens such as EAEC, EHEC, EPEC, ETEC, AIEC and the 2011 German outbreak O104:H4 strain as well as ExPEC such as UPEC and NMEC). We describe additional genes for two membrane-associated DGCs (DgcX, DgcY) and four PDEs (the membrane-associated PdeT as well as the EAL domain-only proteins PdeW, PdeX and PdeY), thus showing the pangenome of E. coli to contain at least 35 GGDEF/EAL domain proteins. A core set of only eight proteins is absolutely conserved in all 61 strains: DgcC (YaiC), DgcI (YliF), PdeB (YlaB), PdeH (YhjH), PdeK (YhjK), PdeN (Rtn) and the degenerate proteins CsrD and CdgI (YeaI). In all other GGDEF/EAL domain genes, diverse point and frame shift mutations as well as small or large deletions were discovered in various strains. Our analysis reveals interesting trends in pathogenic E. coli that could reflect different host cell adherence mechanisms. These may either benefit from or be counteracted by the c-di-GMP-stimulated production of amyloid curli fibres and cellulose. Thus, EAEC - which adhere in a 'stacked brick' biofilm mode - have a potential for high c-di-GMP accumulation due to DgcX, a strongly expressed additional DGC. By contrast, EHEC and UPEC - which use alternative adherence mechanisms - tend to have extra PDEs, suggesting that low cellular c-di-GMP levels are crucial for these strains under some specific conditions. Overall, our study also indicates that GGDEF/EAL domain proteins evolve rapidly and thereby contribute to adaptation to host-specific and environmental niches of various types of E. coli. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of bacteriology 08/2015; DOI:10.1128/JB.00520-15 · 2.69 Impact Factor
  • Diego O Serra · Gisela Klauck · Regine Hengge
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    ABSTRACT: Bacterial macrocolony biofilms grow into intricate three-dimensional structures that depend on self-produced extracellular polymers conferring protection, cohesion and elasticity to the biofilm. In Escherichia coli, synthesis of this matrix - consisting of amyloid curli fibres and cellulose - requires CsgD, a transcription factor regulated by the stationary phase sigma factor RpoS, and occurs in the nutrient-deprived cells of the upper layer of macrocolonies. Is this asymmetric matrix distribution functionally important or is it just a fortuitous byproduct of an unavoidable nutrient gradient? In order to address this question, the RpoS-dependent csgD promoter was replaced by a vegetative promoter. This rewiring of csgD led to CsgD and matrix production in both strata of macrocolonies, with the lower layer transforming into a rigid 'baseplate' of growing, yet curli-connected cells. As a result, the two strata broke apart followed by desiccation and exfoliation of the top layer. By contrast, matrix-free cells at the bottom of wildtype macrocolonies maintain colony contact with the humid agar support by flexibly filling the space that opens up under buckling areas of the macrocolony. Precisely regulated stratification in matrix-free and matrix-producing cell layers is thus essential for the physical integrity and architecture of E. coli macrocolony biofilms. This article is protected by copyright. All rights reserved.
    Environmental Microbiology 07/2015; DOI:10.1111/1462-2920.12991 · 6.24 Impact Factor
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    ABSTRACT: Background: Bacteria have developed a repertoire of signalling mechanisms that enable adaptive responses to fluctuating environmental conditions. The formation of biofilm, for example, allows persisting in times of external stresses, e.g. induced by antibiotics or a lack of nutrients. Adhesive curli fibers, the major extracellular matrix components in Escherichia coli biofilms, exhibit heterogeneous expression in isogenic cells exposed to identical external conditions. The dynamical mechanisms underlying this heterogeneity remain poorly understood. In this work, we elucidate the potential role of post-translational bistability as a source for this heterogeneity. Results: We introduce a structured modelling workflow combining logical network topology analysis with time-continuous deterministic and stochastic modelling. The aim is to evaluate the topological structure of the underlying signalling network and to identify and analyse model parameterisations that satisfy observations from a set of genetic knockout experiments. Our work supports the hypothesis that the phenotypic heterogeneity of curli expression in biofilm cells is induced by bistable regulation at the post-translational level. Stochastic modelling suggests diverse noise-induced switching behaviours between the stable states, depending on the expression levels of the c-di-GMP-producing (diguanylate cyclases, DGCs) and -degrading (phosphodiesterases, PDEs) enzymes and reveals the quantitative difference in stable c-di-GMP levels between distinct phenotypes. The most dominant type of behaviour is characterised by a fast switching from curli-off to curli-on with a slow switching in the reverse direction and the second most dominant type is a long-term differentiation into curli-on or curli-off cells. This behaviour may implicate an intrinsic feature of the system allowing for a fast adaptive response (curli-on) versus a slow transition to the curli-off state, in line with experimental observations. Conclusion: The combination of logical and continuous modelling enables a thorough analysis of different determinants of bistable regulation, i.e. network topology and biochemical kinetics, and allows for an incorporation of experimental data from heterogeneous sources. Our approach yields a mechanistic explanation for the phenotypic heterogeneity of curli fiber expression. Furthermore, the presented work provides a detailed insight into the interactions between the multiple DGC- and PDE-type enzymes and the role of c-di-GMP in dynamical regulation of cellular decisions.
    BMC Systems Biology 07/2015; 9(39). DOI:10.1186/s12918-015-0183-x · 2.85 Impact Factor
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    ABSTRACT: In recent years, Escherichia coli has served as one of a handful of model bacterial species for studying c-di-GMP signaling. The widely used E. coli K-12 laboratory strains possesses 29 genes encoding proteins with GGDEF and/or EAL domains, which include 12 diguanylate cyclases (DGC), 13 c-di-GMP-specific phosphodiesterases (PDE) and four 'degenerate' enzymatically inactive proteins. In addition, six new GGDEF/EAL domain-encoding genes, which encode two DGCs and four PDEs, have recently been found in genomic analyses of commensal and pathogenic E. coli strains. As a group of researchers who have been studying the molecular mechanisms and/or the genomic basis of c-di-GMP signaling in E. coli, we now propose a general and systematic dgc and pde nomenclature for the enzymatically active GGDEF/EAL domain-encoding genes of this model species. This nomenclature is intuitive and easy to memorize and it can also be applied to additional genes and proteins that might be discovered in various strains of E. coli in future studies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of bacteriology 07/2015; DOI:10.1128/JB.00424-15 · 2.69 Impact Factor
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    ABSTRACT: The first 'International Symposium on c-di-GMP Signaling in Bacteria' (March 22 - 25, 2015, Harnack-Haus, Berlin, Germany) brought together 131 molecular microbiologists from 17 countries to discuss recent progress in our knowledge of bacterial nucleotide second messenger signaling. While the focus was on signal input, synthesis, degradation and the striking diversity of the modes of action of the current second messenger paradigm, i.e. c-di-GMP, also 'classics' like cAMP and (p)ppGpp were presented in novel facets and more recent 'newcomers' such as c-di-AMP and c-AMP-GMP made an impressive appearance. A number of clear trends emerged during the 30 talks, on the 71 posters and in the lively discussions, including (i) c-di-GMP control of the activities of various ATPases and phosphorylation cascades; (ii) extensive cross-talk between c-di-GMP and other nucleotide second messenger signaling pathways; and (iii) a stunning number of novel effectors for nucleotide second messengers that surprisingly include some long-known master regulators of developmental pathways. Overall, the conference made it amply clear that second messenger signaling is currently one of the most dynamic fields within molecular microbiology with major impact ranging from human health to microbial ecology. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of bacteriology 06/2015; DOI:10.1128/JB.00331-15 · 2.69 Impact Factor
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    ABSTRACT: In 2011, nearly 4,000 people in Germany were infected by Shiga toxin (Stx)-producing Escherichia coli O104:H4 with > 22% of patients developing haemolytic uraemic syndrome (HUS). Genome sequencing showed the outbreak strain to be related to enteroaggregative E. coli (EAEC), suggesting its high virulence results from EAEC-typical strong adherence and biofilm formation combined to Stx production. Here, we report that the outbreak strain contains a novel diguanylate cyclase (DgcX)—producing the biofilm-promoting second messenger c-di-GMP—that shows higher expression than any other known E. coli diguanylate cyclase. Unlike closely related E. coli, the outbreak strain expresses the c-di-GMP-controlled biofilm regulator CsgD and amyloid curli fibres at 37°C, but is cellulose-negative. Moreover, it constantly generates derivatives with further increased and deregulated production of CsgD and curli. Since curli fibres are strongly proinflammatory, with cellulose counteracting this effect, high c-di-GMP and curli production by the outbreak O104:H4 strain may enhance not only adherence but may also contribute to inflammation, thereby facilitating entry of Stx into the bloodstream and to the kidneys where Stx causes HUS.
    EMBO Molecular Medicine 10/2014; 6(12). DOI:10.15252/emmm.201404309 · 8.25 Impact Factor
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    Franziska Mika · Regine Hengge
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    ABSTRACT: Amyloid curli fibers and cellulose are extracellular matrix components produced in the stationary phase top layer of E. coli macrocolonies, which confer physical protection, strong cohesion, elasticity, and wrinkled morphology to these biofilms. Curli and cellulose synthesis is controlled by a three-level transcription factor (TF) cascade with the RpoS sigma subunit of RNA polymerase at the top, the MerR-like TF MlrA, and the biofilm regulator CsgD, with two c-di-GMP control modules acting as key switching devices. Additional signal input and fine-tuning is provided by an entire series of small RNAs-ArcZ, DsrA, RprA, McaS, OmrA/OmrB, GcvB, and RydC-that differentially control all three TF modules by direct mRNA interaction. This review not only summarizes the mechanisms of action of these sRNAs, but also addresses the question of how these sRNAs and the regulators they target contribute to building the intriguing three-dimensional microarchitecture and macromorphology of these biofilms.
    RNA Biology 04/2014; 11(5). DOI:10.4161/rna.28867 · 5.38 Impact Factor
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    Diego O. Serra · Regine Hengge
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    ABSTRACT: In natural habitats bacteria often occur in multicellular communities characterized by a robust extracellular matrix of proteins, amyloid fibres, exopolysaccharides and extracellular DNA. These biofilms show pronounced stress resistance including a resilience against antibiotics, which causes serious medical and technical problems. This review summarizes recent studies that have revealed clear spatial physiological differentiation, complex supracellular architecture and striking morphology in macrocolony biofilms. By responding to gradients of nutrients, oxygen, waste products and signaling compounds that build up in growing biofilms, various stress responses determine whether bacteria grow and proliferate or whether they enter into stationary phase and use their remaining resources for maintenance and survival. As a consequence, biofilms differentiate into at least two distinct layers of vegetatively growing and stationary phase cells that exhibit very different cellular physiology. This includes a stratification of matrix production with a major impact on microscopic architecture, biophysical properties and directly visible morphology of macrocolony biofilms. Using E. coli as a model system, this review also describes our detailed current knowledge about the underlying molecular control networks – prominently featuring sigma factors, transcriptional cascades and second messengers – that drive this spatial differentiation and points out directions for future research.
    Environmental Microbiology 04/2014; 16(6). DOI:10.1111/1462-2920.12483 · 6.24 Impact Factor
  • Diego O Serra · Anja M Richter · Regine Hengge
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    ABSTRACT: Morphological form in multicellular aggregates emerges from the interplay of genetic constitution and environmental signals. Bacterial macrocolony biofilms, which form intricate three-dimensional structures such as large and often radially oriented ridges, concentric rings and elaborate wrinkles, provide a unique opportunity to understand this interplay of 'nature and nurture' in morphogenesis at the molecular level. Macrocolony morphology depends on self-produced extracellular matrix components. In Escherichia coli, these are stationary phase-induced amyloid curli fibres and cellulose. While the widely used 'domesticated' E. coli K-12 laboratory strains are unable to generate cellulose, we could restore cellulose production and macrocolony morphology of E. coli K-12 strain W3110 by 'repairing' a single chromosomal SNP in the bcs operon. Using scanning electron and fluorescence microscopy, cellulose filaments, sheets and nano-composites with curli fibres were localized in situ at cellular resolution within the physiologically two-layered macrocolony biofilms of this 'de-domesticated' strain. As an architectural element, cellulose confers cohesion and elasticity, i.e. tissue-like properties that - together with the cell-encasing curli fibre network and geometrical constraints in a growing colony - explain the formation of long and high ridges and elaborate wrinkles of wildtype macrocolonies. By contrast, a biofilm matrix consisting of the curli fibre network only is brittle and breaks into a pattern of concentric dome-shaped rings separated by deep crevices. These studies now set the stage for clarifying how regulatory networks and in particular c-di-GMP signaling operate in the three-dimensional space of highly structured and 'tissue-like' bacterial biofilms.
    Journal of bacteriology 10/2013; 195(24). DOI:10.1128/JB.00946-13 · 2.69 Impact Factor
  • Regine Hengge · Victor Sourjik
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    ABSTRACT: The ESF-EMBO Conference on 'Bacterial Networks' (BacNet13) was held in March 2013, in Pultusk, Poland. It brought together 164 molecular microbiologists, bacterial systems biologists and synthetic biologists to discuss the architecture, function and dynamics of regulatory networks in bacteria.
    EMBO Reports 07/2013; 14(8). DOI:10.1038/embor.2013.93 · 7.86 Impact Factor
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    ABSTRACT: C-di-GMP-which is produced by diguanylate cyclases (DGC) and degraded by specific phosphodiesterases (PDEs)-is a ubiquitous second messenger in bacterial biofilm formation. In Escherichia coli, several DGCs (YegE, YdaM) and PDEs (YhjH, YciR) and the MerR-like transcription factor MlrA regulate the transcription of csgD, which encodes a biofilm regulator essential for producing amyloid curli fibres of the biofilm matrix. Here, we demonstrate that this system operates as a signalling cascade, in which c-di-GMP controlled by the DGC/PDE pair YegE/YhjH (module I) regulates the activity of the YdaM/YciR pair (module II). Via multiple direct interactions, the two module II proteins form a signalling complex with MlrA. YciR acts as a connector between modules I and II and functions as a trigger enzyme: its direct inhibition of the DGC YdaM is relieved when it binds and degrades c-di-GMP generated by module I. As a consequence, YdaM then generates c-di-GMP and-by direct and specific interaction-activates MlrA to stimulate csgD transcription. Trigger enzymes may represent a general principle in local c-di-GMP signalling.
    The EMBO Journal 05/2013; 32(14). DOI:10.1038/emboj.2013.120 · 10.75 Impact Factor
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    Franziska Mika · Regine Hengge
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    ABSTRACT: Biofilm formation in Escherichia coli and other enteric bacteria involves the inverse regulation of the synthesis of flagella and biofilm matrix components such as amyloid curli fibres, cellulose, colanic acid and poly-N-acetylglucosamine (PGA). Physiologically, these processes reflect the transition from growth to stationary phase. At the molecular level, they are tightly controlled by various sigma factors competing for RNA polymerase, a series of transcription factors acting in hierarchical regulatory cascades and several nucleotide messengers, including cyclic-di-GMP. In addition, a surprisingly large number of small regulatory RNAs (sRNAs) have been shown to directly or indirectly modulate motility and/or biofilm formation. This review aims at giving an overview of these sRNA regulators and their impact in biofilm formation in E. coli and Salmonella. Special emphasis will be put on sRNAs, that have known targets such as the mRNAs of the flagellar master regulator FlhDC, the stationary phase sigma factor σS (RpoS) and the key biofilm regulator CsgD that have recently been shown to act as major hubs for regulation by multiple sRNAs.
    International Journal of Molecular Sciences 03/2013; 14(3):4560-79. DOI:10.3390/ijms14034560 · 2.86 Impact Factor
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    Regine Hengge
    mBio 02/2013; 4(2). DOI:10.1128/mBio.00245-13 · 6.88 Impact Factor
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    ABSTRACT: Bacterial biofilms are highly structured multicellular communities whose formation involves flagella and an extracellular matrix of adhesins, amyloid fibers, and exopolysaccharides. Flagella are produced by still-dividing rod-shaped Escherichia coli cells during postexponential growth when nutrients become suboptimal. Upon entry into stationary phase, however, cells stop producing flagella, become ovoid, and generate amyloid curli fibers. These morphological changes, as well as accompanying global changes in gene expression and cellular physiology, depend on the induction of the stationary-phase sigma subunit of RNA polymerase, σS (RpoS), the nucleotide second messengers cyclic AMP (cAMP), ppGpp, and cyclic-di-GMP, and a biofilm-controlling transcription factor, CsgD. Using flagella, curli fibers, a CsgD::GFP reporter, and cell morphology as “anatomical” hallmarks in fluorescence and scanning electron microscopy, different physiological zones in macrocolony biofilms of E. coli K-12 can be distinguished at cellular resolution. Small ovoid cells encased in a network of curli fibers form the outer biofilm layer. Inner regions are characterized by heterogeneous CsgD::GFP and curli expression. The bottom zone of the macrocolonies features elongated dividing cells and a tight mesh of entangled flagella, the formation of which requires flagellar motor function. Also, the cells in the outer-rim growth zone produce flagella, which wrap around and tether cells together. Adjacent to this growth zone, small chains and patches of shorter curli-surrounded cells appear side by side with flagellated curli-free cells before curli coverage finally becomes confluent, with essentially all cells in the surface layer being encased in “curli baskets.”
    mBio 02/2013; 4(2). DOI:10.1128/mBio.00103-13 · 6.88 Impact Factor
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    Regine Hengge
    The EMBO Journal 01/2013; DOI:10.1038/emboj.2012.351 · 10.75 Impact Factor
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    ABSTRACT: In response to the 2011 European health alert caused by a pathogenic Escherichia coli O104:H4 outbreak, the European Academy of Microbiology (EAM), established by the Federation of European Microbiological Societies (FEMS), convened a meeting in Paris on November 30th, 2011 on 'EHEC infection and control' attended by world renowned experts in pathogenic E. coli. The major aims of this group were to review the scientific issues raised by the outbreak, to assess the handling of the crisis at the scientific and political levels, and to propose future actions. Several conclusions, which will have impact on future potential E. coli outbreaks, are outlined here.
    EMBO Molecular Medicine 09/2012; 4(9):841-8. DOI:10.1002/emmm.201201662 · 8.25 Impact Factor
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    Natalia Tschowri · Sandra Lindenberg · Regine Hengge
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    ABSTRACT: Escherichia coli senses blue light via the BLUF-EAL protein BluF (YcgF). The degenerate EAL domain of BluF does not have cyclic-di-GMP phosphodiesterase activity, but BluF directly antagonizes the MerR-like repressor BluR (YcgE), which leads to expression of the ycgZ-ymgABC operon and activation of the Rcs system (Tschowri et al., 2009; Genes Dev 23: 522-534). While bluR, bluF and ycgZ have individual transcriptional start sites, comparative genome analysis indicates that the bluR-bluF-ycgZ-ymgAB region represents a functional unit in various enteric bacteria that is characterized by bluF alleles encoding degenerate EAL domains. Re-introducing conserved amino acids involved in phosphodiesterase activity of EAL domains did not restore enzymatic activity or c-di-GMP binding of BluF, but weakened its ability to antagonize BluR and improved a residual interaction with the BluR paralogue MlrA, which controls expression of the biofilm regulator CsgD and curli fibres. We identified the BluR binding site in the ycgZ promoter and observed that BluR also has residual affinity for the MlrA-dependent csgD promoter. Altogether, we propose that BluF evolved from a blue light-regulated PDE into a specific antagonist of a duplicate of MlrA that became BluR, which controls not only curli but various biofilm functions via the Ymg/Rcs pathway.
    Molecular Microbiology 07/2012; 85(5):893-906. DOI:10.1111/j.1365-2958.2012.08147.x · 5.03 Impact Factor
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    ABSTRACT: RprA is a small regulatory RNA known to weakly affect the translation of σ(S) (RpoS) in Escherichia coli. Here we demonstrate that csgD, which encodes a stationary phase-induced biofilm regulator, as well as ydaM, which encodes a diguanylate cyclase involved in activating csgD transcription, are novel negatively controlled RprA targets. As shown by extensive mutational analysis, direct binding of RprA to the 5'-untranslated and translational initiation regions of csgD mRNA inhibits translation and reduces csgD mRNA levels. In the case of ydaM mRNA, RprA base-pairs directly downstream of the translational start codon. In a feedforward loop, RprA can thus downregulate > 30 YdaM/CsgD-activated genes including those for adhesive curli fimbriae. However, during early stationary phase, when csgD transcription is strongly activated, the synthesis of csgD mRNA exceeds that of RprA, which allows the accumulation of CsgD protein. This situation is reversed when csgD transcription is shut off - for instance, later in stationary phase or during biofilm formation - or by conditions that further activate RprA expression via the Rcs two-component system. Thus, antagonistic regulation of csgD and RprA at the mRNA level integrates cell envelope stress signals with global gene expression during stationary phase and biofilm formation.
    Molecular Microbiology 02/2012; 84(1):51-65. DOI:10.1111/j.1365-2958.2012.08002.x · 5.03 Impact Factor
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    Christina Pesavento · Regine Hengge
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    ABSTRACT: FliZ, a global regulatory protein under the control of the flagellar master regulator FlhDC, was shown to antagonize σ(S)-dependent gene expression in Escherichia coli. Thereby it plays a pivotal role in the decision between alternative life-styles, i.e. FlhDC-controlled flagellum-based motility or σ(S)-dependent curli fimbriae-mediated adhesion and biofilm formation. Here, we show that FliZ is an abundant DNA-binding protein that inhibits gene expression mediated by σ(S) by recognizing operator sequences that resemble the -10 region of σ(S)-dependent promoters. FliZ does so with a structural element that is similar to region 3.0 of σ(S). Within this element, R108 in FliZ corresponds to K173 in σ(S), which contacts a conserved cytosine at the -13 promoter position that is specific for σ(S)-dependent promoters. R108 as well as C(-13) are also crucial for DNA binding by FliZ. However, while a number of FliZ binding sites correspond to known σ(S)-dependent promoters, promoter activity is not a prerequisite for FliZ binding and repressor function. Thus, we demonstrate that FliZ also feedback-controls flagellar gene expression by binding to a site in the flhDC control region that shows similarity only to a -10 element of a σ(S)-dependent promoter, but does not function as a promoter.
    Nucleic Acids Research 02/2012; 40(11):4783-93. DOI:10.1093/nar/gks055 · 9.11 Impact Factor
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    ABSTRACT: In response to the 2011 European health alert caused by a pathogenic Escherichia coli O104:H4 outbreak, the European Academy of Microbiology (EAM), established by the Federation of European Microbiological Societies (FEMS), convened a meeting in Paris on November 30th, 2011 on ‘EHEC infection and control’ attended by world renowned experts in pathogenic E. coli. The major aims of this group were to review the scientific issues raised by the outbreak, to assess the handling of the crisis at the scientific and political levels, and to propose future actions. Several conclusions, which will have impact on future potential E. coli outbreaks, are outlined here.
    EMBO Molecular Medicine 01/2012; 4(9). · 8.25 Impact Factor

Publication Stats

3k Citations
325.22 Total Impact Points

Institutions

  • 2014
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2003–2013
    • Freie Universität Berlin
      • Institute of Biology
      Berlín, Berlin, Germany
  • 2005
    • Forschungszentrum Jülich
      Jülich, North Rhine-Westphalia, Germany