TsrA Regulates Virulence and Intestinal Colonization in
            <i>Vibrio cholerae</i>

DuPai, Cory D.; Cunningham, Ashley L.; Conrado, Aaron R.; Wilke, Claus O.; Davies, Bryan William

doi:10.1128/msphere.01014-20

“…The p.Thr629Met mutation in the patient lies in the beta hairpin of LeuRS between strands I-I of the LS domains and leads to the disruption of the motif and protein stability. This is in accordance with the observation that beta hairpin motifs are implicated in protein stability 29 , 30 . Moreover, the substitution of p.Ala508 in Escherichia coli LeuRS (analogous to human LeuRS p.Thr629) with a nonpolar methionine disrupts the structure and/or position of the leucine-specific domain and thus shifts the location of the KMSKS loop and reduces the catalytic efficiency 16 , 31 .…”

Section: Discussionsupporting

confidence: 92%

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

Buonfiglio

¹

,

Bruque²,

Lotersztein

³

et al. 2022

Sci Rep

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Hearing loss is a heterogeneous disorder. Identification of causative mutations is demanding due to genetic heterogeneity. In this study, we investigated the genetic cause of sensorineural hearing loss in patients with severe/profound deafness. After the exclusion of GJB2-GJB6 mutations, we performed whole exome sequencing in 32 unrelated Argentinean families. Mutations were detected in 16 known deafness genes in 20 patients: ACTG1, ADGRV1 (GPR98), CDH23, COL4A3, COL4A5, DFNA5 (GSDDE), EYA4, LARS2, LOXHD1, MITF, MYO6, MYO7A, TECTA, TMPRSS3, USH2A and WSF1. Notably, 11 variants affecting 9 different non-GJB2 genes resulted novel: c.12829C > T, p.(Arg4277*) in ADGRV1; c.337del, p.(Asp109*) and c.3352del, p.(Gly1118Alafs*7) in CDH23; c.3500G > A, p.(Gly1167Glu) in COL4A3; c.1183C > T, p.(Pro395Ser) and c.1759C > T, p.(Pro587Ser) in COL4A5; c.580 + 2 T > C in EYA4; c.1481dup, p.(Leu495Profs*31) in LARS2; c.1939 T > C, p.(Phe647Leu), in MYO6; c.733C > T, p.(Gln245*) in MYO7A and c.242C > G, p.(Ser81*) in TMPRSS3 genes. To predict the effect of these variants, novel protein modeling and protein stability analysis were employed. These results highlight the value of whole exome sequencing to identify candidate variants, as well as bioinformatic strategies to infer their pathogenicity.

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“…Consistent with previous studies [44,45], we observe that the regulons of both H-NS and TsrA are both AT-rich, which is a characteristic of many horizontally acquired elements and targets of H-NS in gamma-proteobacteria (Supplementary Figure 6B).…”

Section: Ple Genes Log2fc Insupporting

confidence: 91%

“…StpA, which binds directly to DNA [26], TsrA has not been predicted to have DNAbinding ability [44][45][46], suggesting it may function through H-NS and/or another protein.…”

Section: Ple Genes Log2fc Inmentioning

confidence: 99%

“…Recent transcriptomic studies have demonstrated that TsrA, a protein with weak amino acid homology to H-NS, is involved in transcriptional regulation [44,45]. However, based on previous computational modeling and bioinformatics analysis, TsrA does not have a predicted DNA binding domain [44][45][46].…”

Section: Introductionmentioning

confidence: 99%

“…Recent transcriptomic studies have demonstrated that TsrA, a protein with weak amino acid homology to H-NS, is involved in transcriptional regulation [44,45]. However, based on previous computational modeling and bioinformatics analysis, TsrA does not have a predicted DNA binding domain [44][45][46]. While previous studies measured the separate effects of hns and tsrA deletions on gene expression [44,45] and identified a strong overlap in the regulons of H-NS and TsrA, the combinatorial effects of H-NS and TsrA on global protein occupancy and gene expression have not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Nucleoid-associated proteins shape the global protein occupancy and transcriptional landscape of a clinical isolate ofVibrio cholerae

Rakibova,

Dunham,

Seed

et al. 2024

Preprint

1

0

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Vibrio cholerae, the causative agent of the diarrheal disease cholera, poses an ongoing health threat due to its wide repertoire of horizontally acquired elements (HAEs) and virulence factors. New clinical isolates of the bacterium with improved fitness abilities, often associated with HAEs, frequently emerge. The appropriate control and expression of such genetic elements is critical for the bacteria to thrive in the different environmental niches it occupies. H-NS, the histone-like nucleoid structuring protein, is the best studied xenogeneic silencer of HAEs in gamma-proteobacteria. Although H-NS and other highly abundant nucleoid-associated proteins (NAPs) have been shown to play important roles in regulating HAEs and virulence in model bacteria, we still lack a comprehensive understanding of how different NAPs modulate transcription in V. cholerae. By obtaining genome-wide measurements of protein occupancy and active transcription in a clinical isolate of V. cholerae, harboring recently discovered HAEs encoding for phage defense systems, we show that a lack of H-NS causes a robust increase in the expression of genes found in many HAEs. We further found that TsrA, a protein with partial homology to H-NS, regulates virulence genes primarily through modulation of H-NS activity. We also identified a few sites that are affected by TsrA independently of H-NS, suggesting TsrA may act with diverse regulatory mechanisms. Our results demonstrate how the combinatorial activity of NAPs is employed by a clinical isolate of an important pathogen to regulate recently discovered HAEs.

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Nucleoid-associated proteins shape the global protein occupancy and transcriptional landscape of a clinical isolate of Vibrio cholerae

Rakibova,

Dunham,

Seed

et al. 2024

mSphere

0

View full text Add to dashboard Cite

Vibrio cholerae, the causative agent of the diarrheal disease cholera, poses an ongoing health threat due to its wide repertoire of horizontally acquired elements (HAEs) and virulence factors. New clinical isolates of the bacterium with improved fitness abilities, often associated with HAEs, frequently emerge. The appropriate control and expression of such genetic elements is critical for the bacteria to thrive in the different environmental niches they occupy. H-NS, the histone-like nucleoid structuring protein, is the best-studied xenogeneic silencer of HAEs in gamma-proteobacteria. Although H-NS and other highly abundant nucleoid-associated proteins (NAPs) have been shown to play important roles in regulating HAEs and virulence in model bacteria, we still lack a comprehensive understanding of how different NAPs modulate transcription in V. cholerae . By obtaining genome-wide measurements of protein occupancy and active transcription in a clinical isolate of V. cholerae, harboring recently discovered HAEs encoding for phage defense systems, we show that a lack of H-NS causes a robust increase in the expression of genes found in many HAEs. We further found that TsrA, a protein with partial homology to H-NS, regulates virulence genes primarily through modulation of H-NS activity. We also identified few sites that are affected by TsrA independently of H-NS, suggesting TsrA may act with diverse regulatory mechanisms. Our results demonstrate how the combinatorial activity of NAPs is employed by a clinical isolate of an important pathogen to regulate recently discovered HAEs. IMPORTANCE New strains of the bacterial pathogen Vibrio cholerae , bearing novel horizontally acquired elements (HAEs), frequently emerge. HAEs provide beneficial traits to the bacterium, such as antibiotic resistance and defense against invading bacteriophages. Xenogeneic silencers are proteins that help bacteria harness new HAEs and silence those HAEs until they are needed. H-NS is the best-studied xenogeneic silencer; it is one of the nucleoid-associated proteins (NAPs) in gamma-proteobacteria and is responsible for the proper regulation of HAEs within the bacterial transcriptional network. We studied the effects of H-NS and other NAPs on the HAEs of a clinical isolate of V. cholerae . Importantly, we found that H-NS partners with a small and poorly characterized protein, TsrA, to help domesticate new HAEs involved in bacterial survival and in causing disease. A proper understanding of the regulatory state in emerging isolates of V. cholerae will provide improved therapies against new isolates of the pathogen.

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TsrA Regulates Virulence and Intestinal Colonization in Vibrio cholerae

Cited by 3 publications

References 51 publications

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

Nucleoid-associated proteins shape the global protein occupancy and transcriptional landscape of a clinical isolate ofVibrio cholerae

Nucleoid-associated proteins shape the global protein occupancy and transcriptional landscape of a clinical isolate of Vibrio cholerae

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