The leucine-responsive regulatory proteins/feast-famine regulatory proteins: an ancient and complex class of transcriptional regulators in bacteria and archaea

Ziegler, Christine A; Freddolino, Peter L.

doi:10.1080/10409238.2021.1925215

Cited by 30 publications

(30 citation statements)

References 141 publications

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“…It was suggested that differential virulence of Xenorhabdus strains (demonstrated in Figure 5 ) must be caused by the difference in the global leucine-responsive regulatory protein expression level metabolites [ 106 , 107 , 108 , 109 , 110 ], leading to a difference in the production of indole compounds, and other NRPS-PKS-associated secondary metabolites [ 106 ].…”

Section: Coevolution and Co-speciation Of Epn/epb Symbiotic Associationsmentioning

confidence: 99%

Type Strains of Entomopathogenic Nematode-Symbiotic Bacterium Species, Xenorhabdus szentirmaii (EMC) and X. budapestensis (EMA), Are Exceptional Sources of Non-Ribosomal Templated, Large-Target-Spectral, Thermotolerant-Antimicrobial Peptides (by Both), and Iodinin (by EMC)

Fodor

Gualtieri²,

Zeller

et al. 2022

Pathogens

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Antimicrobial multidrug resistance (MDR) is a global challenge, not only for public health, but also for sustainable agriculture. Antibiotics used in humans should be ruled out for use in veterinary or agricultural settings. Applying antimicrobial peptide (AMP) molecules, produced by soil-born organisms for protecting (soil-born) plants, seems a preferable alternative. The natural role of peptide-antimicrobials, produced by the prokaryotic partner of entomopathogenic-nematode/bacterium (EPN/EPB) symbiotic associations, is to sustain monoxenic conditions for the EPB in the gut of the semi-anabiotic infective dauer juvenile (IJ) EPN. They keep pathobiome conditions balanced for the EPN/EPB complex in polyxenic (soil, vanquished insect cadaver) niches. Xenorhabdus szentirmaii DSM16338(T) (EMC), and X. budapestensis DSM16342(T) (EMA), are the respective natural symbionts of EPN species Steinernema rarum and S. bicornutum. We identified and characterized both of these 15 years ago. The functional annotation of the draft genome of EMC revealed 71 genes encoding non-ribosomal peptide synthases, and polyketide synthases. The large spatial Xenorhabdus AMP (fabclavine), was discovered in EMA, and its biosynthetic pathway in EMC. The AMPs produced by EMA and EMC are promising candidates for controlling MDR prokaryotic and eukaryotic pathogens (bacteria, oomycetes, fungi, protozoa). EMC releases large quantity of iodinin (1,6-dihydroxyphenazine 5,10-dioxide) in a water-soluble form into the media, where it condenses to form spectacular water-insoluble, macroscopic crystals. This review evaluates the scientific impact of international research on EMA and EMC.

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Section: Coevolution and Co-speciation Of Epn/epb Symbiotic Associationsmentioning

confidence: 99%

Type Strains of Entomopathogenic Nematode-Symbiotic Bacterium Species, Xenorhabdus szentirmaii (EMC) and X. budapestensis (EMA), Are Exceptional Sources of Non-Ribosomal Templated, Large-Target-Spectral, Thermotolerant-Antimicrobial Peptides (by Both), and Iodinin (by EMC)

Fodor

Gualtieri²,

Zeller

et al. 2022

Pathogens

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“…Across all FFRPs, four small molecule effector binding sites have been identified [22]. Two such sites (Type I and Type III) are found in E. coli Lrp, where the Type I site is the highly conserved high-affinity effector binding site and Type III is less conserved and serves as a low-affinity effector binding site [6]. Previous studies have reported that residue D114 in Lrp is part of the low-affinity site and contributes to higher-order Lrp oligomerization [13].…”

Section: Discussionmentioning

confidence: 99%

“…It is also useful to consider the clustering of Lrp binding regions (Y-axis of Fig. 2B), which separate into eight distinct classes (1)(2)(3)(4)(5)(6)(7)(8). Class 1 consists of WT and D114E Min-Stat specific sites.…”

Section: Paired Lrp-and Rnap-chip Seq Reproduce Previous Findings And...mentioning

confidence: 99%

“…Of these global regulators, Lrp ( L eucine-responsive R egulatory P rotein) is of particular interest due to its crucial role in nutrient sensing and its high conservation among prokaryotes; nearly half of sequenced bacteria and almost all sequenced archaea contain one or more Lrp homologs [3]. While Lrp was originally identified in 1973 by the Oxender Lab [4] and has since been shown to regulate as many as 32% of E. coli genes either directly or indirectly [5], little is known about the precise mechanism by which Lrp regulates its target genes [6].…”

Section: Introductionmentioning

confidence: 99%

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E. coli Leucine-responsive regulatory protein bridges DNA in vivo and tunably dissociates in the presence of exogenous leucine

Ziegler

Freddolino

2022

Preprint

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Feast-Famine Response Proteins are a widely conserved class of global regulators in prokaryotes, the most highly studied of which is the E. coli leucine-responsive regulatory protein (Lrp). Lrp senses environmental nutrition status and subsequently regulates up to one-third of the genes in E. coli, either directly or indirectly. Lrp exists predominantly as octamers and hexadecamers (16mers), where leucine is believed to shift the equilibrium towards the octameric state. In this study, we analyzed the effects of three oligomerization state mutants of Lrp in terms of their ability to bind to DNA and regulate gene expression in response to exogenous leucine. We find that oligomerization beyond dimers is required for Lrp's regulatory activity, and that contrary to prior speculation, exogenous leucine modulates Lrp activity at its target promoters exclusively by inhibiting Lrp binding to DNA. We also find evidence that Lrp binding bridges DNA over length scales of multiple kilobases, revealing a new range of mechanisms for Lrp-mediated transcriptional regulation.

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“…Lrp binds cooperatively to DNA [Chen et al, 2005] at sites matching a degenerate consensus sequence [Cui et al, 1999], its 8-mer/16-mer oligomeric structure is sensitive to L-leucine [Chen and Calvo, 2002] and its gene regulatory activities may be indifferent to, stimulated by, or inhibited by, L-leucine and other amino acids [Calvo and Matthews, 1994; Chen et al, 2001; Ziegler and Freddolino, 2021]. The production of Lrp is subject to transcriptional autorepression [McFarland and Dorman, 2008; Wang et al, 1994]; it has a broad impact on gene expression [Cho et al, 2008], and plays a central part in the adaptation of the bacterium to the stationary phase of the growth cycle [Kroner et al, 2019; Tani et al, 2002; Zinser et al, 2000].…”

Section: Introductionmentioning

confidence: 99%

The DNA-relaxation-dependent Off-to-On biasing of the type 1 fimbrial genetic switch requires the Fis nucleoid-associated protein

Conway

Beckett

Dorman

2022

Preprint

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The structural genes expressing type 1 fimbriae in Escherichia coli alternate between expressed (phase ON) and non-expressed (phase OFF) states due to inversion of the 314-bp fimS genetic switch. The FimB tyrosine integrase inverts fimS by site-specific recombination, alternately connecting and disconnecting the fim operon, encoding the fimbrial subunit protein and its associated secretion and adhesin factors, to and from its transcriptional promoter within fimS. Site-specific recombination by the FimB recombinase becomes biased towards phase ON as DNA supercoiling is relaxed, a condition that occurs when bacteria approach the stationary phase of the growth cycle. This effect can be mimicked in exponential phase cultures by inhibiting the negative DNA supercoiling activity of DNA gyrase. We report that this bias towards phase ON depends on the presence of the Fis nucleoid-associated protein. We mapped the Fis binding to a site within the invertible fimS switch by DNase I footprinting. Disruption of this binding site by base substitution mutagenesis abolishes both Fis binding and the ability of the mutated switch to sustain its phase ON bias when DNA is relaxed, even in bacteria that produce the Fis protein. In addition, the Fis binding site overlaps one of the sites used by the Lrp protein, a known directionality determinant of fimS inversion that also contributes to phase ON bias. The Fis-Lrp relationship at fimS is reminiscent of that between Fis and Xis when promoting DNA-relaxation-dependent excision of bacteriophage λ from the E. coli chromosome. However, unlike the co-binding mechanism used by Fis and Xis at λ attR, the Fis-Lrp relationship at fimS involves competitive binding. We discuss these findings in the context of the link between fimS inversion biasing and the physiological state of the bacterium.

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The leucine-responsive regulatory proteins/feast-famine regulatory proteins: an ancient and complex class of transcriptional regulators in bacteria and archaea

Cited by 30 publications

References 141 publications

Type Strains of Entomopathogenic Nematode-Symbiotic Bacterium Species, Xenorhabdus szentirmaii (EMC) and X. budapestensis (EMA), Are Exceptional Sources of Non-Ribosomal Templated, Large-Target-Spectral, Thermotolerant-Antimicrobial Peptides (by Both), and Iodinin (by EMC)

Type Strains of Entomopathogenic Nematode-Symbiotic Bacterium Species, Xenorhabdus szentirmaii (EMC) and X. budapestensis (EMA), Are Exceptional Sources of Non-Ribosomal Templated, Large-Target-Spectral, Thermotolerant-Antimicrobial Peptides (by Both), and Iodinin (by EMC)

E. coli Leucine-responsive regulatory protein bridges DNA in vivo and tunably dissociates in the presence of exogenous leucine

The DNA-relaxation-dependent Off-to-On biasing of the type 1 fimbrial genetic switch requires the Fis nucleoid-associated protein

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