scholarly journals Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1524
Author(s):  
Eiji Ishii ◽  
Yoko Eguchi
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Response Regulator ◽  
Signal Perception ◽  
Expression Of Genes ◽  
Two Component Signal Transduction ◽  
Sense And Respond ◽  
Cognate Response Regulator ◽  
And Control ◽  
Novel Drug

Two-component signal transduction systems (TCSs) are widely conserved in bacteria to respond to and adapt to the changing environment. Since TCSs are also involved in controlling the expression of virulence, biofilm formation, quorum sensing, and antimicrobial resistance in pathogens, they serve as candidates for novel drug targets. TCSs consist of a sensor histidine kinase (HK) and its cognate response regulator (RR). Upon perception of a signal, HKs autophosphorylate their conserved histidine residues, followed by phosphotransfer to their partner RRs. The phosphorylated RRs mostly function as transcriptional regulators and control the expression of genes necessary for stress response. HKs sense their specific signals not only in their extracytoplasmic sensor domain but also in their cytoplasmic and transmembrane domains. The signals are sensed either directly or indirectly via cofactors and accessory proteins. Accumulating evidence shows that a single HK can sense and respond to multiple signals in different domains. The underlying molecular mechanisms of how HK activity is controlled by these signals have been extensively studied both biochemically and structurally. In this article, we introduce the wide diversity of signal perception in different domains of HKs, together with their recently clarified structures and molecular mechanisms.

scholarly journals Genetic Analysis of Azole Resistance by Transposon Mutagenesis in Saccharomyces cerevisiae

1999 ◽  
Vol 43 (11) ◽  
pp. 2731-2735 ◽  
Author(s):  
D. P. Kontoyiannis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Screening Tool ◽  
Transposon Mutagenesis ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Recessive Mutations ◽  
Novel Drug ◽  
Novel Drug Targets

ABSTRACT The increasing resistance of Candida species to fluconazole is cause for concern. To determine the molecular mechanisms involved in resistance to fluconazole, I used a scheme of transposon mutagenesis in Saccharomyces cerevisiae, a genetically tractable yeast that is closely related to Candida albicans. This technique, which permits the generation and analysis of multiple random Tn3::LEU2::lacZfusions, can be used as a disruption mutagen (N. B. Burns et al., Genes Dev. 8:1087–1105, 1994). By using the Tn3::LEU2::lacZlibrary as a disruption mutagen, I found recessive mutations in genes that were previously found to be involved in azole resistance, e.g.,PDR5 and CPR1, and in genes previously found to be involved in azole sensitivity, e.g., ERG3. This approach also enabled me to identify recessive mutations in three genes not previously known to be involved in azole sensitivity. Two of the genes,ADA3 and SPT7, are general transcriptional regulators; the third, YMR034c, is a putative sterol transporter. Finally, by screening the Tn3::LEU2::lacZlibrary for lacZ fusions induced by a low concentration of fluconazole, I identified genes known to be induced by azoles as well as a variety of other genes not previously known to be induced by the drug. In conclusion, transposon mutagenesis is a promising screening tool for use in identifying novel drug targets and in uncovering the mechanisms involved in the response of S. cerevisiae to antifungal drugs.

scholarly journals Conversion of Norepinephrine to 3,4-Dihdroxymandelic Acid in Escherichia coli Requires the QseBC Quorum-Sensing System and the FeaR Transcription Factor

2017 ◽  
Vol 200 (1) ◽  
Author(s):  
Sasikiran Pasupuleti ◽  
Nitesh Sule ◽  
Michael D. Manson ◽  
Arul Jayaraman
Keyword(s):  
Escherichia Coli ◽  
Transcription Factor ◽  
Quorum Sensing ◽  
Aromatic Amines ◽  
Response Regulator ◽  
Content Type ◽  
E Coli ◽  
Expression Of Genes ◽  
K 12 ◽  
Cognate Response Regulator

ABSTRACTThe detection of norepinephrine (NE) as a chemoattractant byEscherichia colistrain K-12 requires the combined action of the TynA monoamine oxidase and the FeaB aromatic aldehyde dehydrogenase. The role of these enzymes is to convert NE into 3,4-dihydroxymandelic acid (DHMA), which is a potent chemoattractant sensed by the Tsr chemoreceptor. These two enzymes must be induced by prior exposure to NE, and cells that are exposed to NE for the first time initially show minimal chemotaxis toward it. The induction of TynA and FeaB requires the QseC quorum-sensing histidine kinase, and the signaling cascade requires new protein synthesis. Here, we demonstrate that the cognate response regulator for QseC, the transcription factor QseB, is also required for induction. The related quorum-sensing kinase QseE appears not to be part of the signaling pathway, but its cognate response regulator, QseF, which is also a substrate for phosphotransfer from QseC, plays a nonessential role. The promoter of thefeaRgene, which encodes a transcription factor that has been shown to be essential for the expression oftynAandfeaB, has two predicted QseB-binding sites. One of these sites appears to be in an appropriate position to stimulate transcription from the P1promoter of thefeaRgene. This study unites two well-known pathways: one for expression of genes regulated by catecholamines (QseBC) and one for expression of genes required for metabolism of aromatic amines (FeaR, TynA, and FeaB). This cross talk allowsE. colito convert the host-derived and chemotactically inert NE into the potent bacterial chemoattractant DHMA.IMPORTANCEThe chemotaxis ofE. coliK-12 to norepinephrine (NE) requires the conversion of NE to 3,4-dihydroxymandleic acid (DHMA), and DHMA is both an attractant and inducer of virulence gene expression for a pathogenic enterohemorrhagicE. coli(EHEC) strain. The induction of virulence by DHMA and NE requires QseC. The results described here show that the cognate response regulator for QseC, QseB, is also required for conversion of NE into DHMA. Production of DHMA requires induction of a pathway involved in the metabolism of aromatic amines. Thus, the QseBC sensory system provides a direct link between virulence and chemotaxis, suggesting that chemotaxis to host signaling molecules may require that those molecules are first metabolized by bacterial enzymes to generate the actual chemoattractant.

scholarly journals miR-21 blocks obesity in mice: a potential therapy for humans

2020 ◽  
Author(s):  
Said Lhamyani ◽  
Adriana-Mariel Gentile ◽  
Rosa M. Giráldez-Pérez ◽  
Mónica Feijóo-Cuaresma ◽  
Silvana Yanina Romero-Zerbo ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Drug Targets ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Caloric Intake ◽  
Physiological Role ◽  
Expression Of Genes ◽  
Obesity In Mice ◽  
Metabolically Healthy

AbstractmicroRNAs are promising drug targets in obesity and metabolic disorders. miR-21 expression is upregulated in obese white adipose tissue (WAT); however, its physiological role in WAT has not been fully explored. We aimed to dissect the underlying molecular mechanisms of miR-21 in treating obesity, diabetes, and insulin resistance. We demonstrated, in human and mice, that elevated miR-21 expression is associated with metabolically healthy obesity. miR-21 mimic affected the expression of genes associated with adipogenesis, thermogenesis, and browning in 3T3-L1 adipocytes. In addition, it blocked high fat diet-induced weight gain in obese mice, without modifying food intake or physical activity. This was associated with metabolic enhancements, WAT browning and thermogenic programming, and brown AT induction through VEGF-A, p53, and TGFβ1 signaling pathways. Our findings add a novel role of miR-21 in the regulation of obesity and a potential therapy for both obesity and T2D without altering caloric intake and physical activities.

scholarly journals Two-Component Systems of S. aureus: Signaling and Sensing Mechanisms

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 34
Author(s):  
Lisa Bleul ◽  
Patrice Francois ◽  
Christiane Wolz
Keyword(s):  
Transcriptional Activation ◽  
Drug Targets ◽  
Bacterial Survival ◽  
Histidine Kinases ◽  
Signal Perception ◽  
Signaling Mechanisms ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Sense And Respond

Staphylococcus aureus encodes 16 two-component systems (TCSs) that enable the bacteria to sense and respond to changing environmental conditions. Considering the function of these TCSs in bacterial survival and their potential role as drug targets, it is important to understand the exact mechanisms underlying signal perception. The differences between the sensing of appropriate signals and the transcriptional activation of the TCS system are often not well described, and the signaling mechanisms are only partially understood. Here, we review present insights into which signals are sensed by histidine kinases in S. aureus to promote appropriate gene expression in response to diverse environmental challenges.

scholarly journals The Two-Component Sensor KinB Acts as a Phosphatase To Regulate Pseudomonas aeruginosa Virulence

2012 ◽  
Vol 194 (23) ◽  
pp. 6537-6547 ◽  
Author(s):  
Nikhilesh S. Chand ◽  
Anne E. Clatworthy ◽  
Deborah T. Hung
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Response Regulator ◽  
Opportunistic Pathogen ◽  
Regulatory Control ◽  
Primary Role ◽  
Chronic Infections ◽  
Content Type ◽  
Two Component ◽  
Sense And Respond ◽  
Cognate Response Regulator

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that is capable of causing both acute and chronic infections.P. aeruginosavirulence is subject to sophisticated regulatory control by two-component systems that enable it to sense and respond to environmental stimuli. We recently reported that the two-component sensor KinB regulates virulence in acuteP. aeruginosainfection. Furthermore, it regulates acute-virulence-associated phenotypes such as pyocyanin production, elastase production, and motility in a manner independent of its kinase activity. Here we show that KinB regulates virulence through the global sigma factor AlgU, which plays a key role in repressingP. aeruginosaacute-virulence factors, and through its cognate response regulator AlgB. However, we show that rather than phosphorylating AlgB, KinB's primary role in the regulation of virulence is to act as a phosphatase to dephosphorylate AlgB and alleviate phosphorylated AlgB's repression of acute virulence.

scholarly journals The Spatial Organization of the VirR Boxes Is Critical for VirR-Mediated Expression of the Perfringolysin O Gene, pfoA, from Clostridium perfringens

2004 ◽  
Vol 186 (11) ◽  
pp. 3321-3330 ◽  
Author(s):  
Jackie K. Cheung ◽  
Bruno Dupuy ◽  
Deanna S. Deveson ◽  
Julian I. Rood
Keyword(s):  
Clostridium Perfringens ◽  
Transcriptional Activation ◽  
Spatial Organization ◽  
Response Regulator ◽  
Toxin Production ◽  
Reporter System ◽  
Perfringolysin O ◽  
Target Dna ◽  
Two Component Signal Transduction ◽  
Cognate Response Regulator

ABSTRACT The transcriptional regulation of toxin production in the gram-positive anaerobe Clostridium perfringens involves a two-component signal transduction system that comprises the VirS sensor histidine kinase and its cognate response regulator, VirR. Previous studies showed that VirR binds independently to a pair of imperfect direct repeats, now designated VirR box 1 and VirR box 2, located immediately upstream of the promoter of the pfoA gene, which encodes the cholesterol-dependent cytolysin, perfringolysin O. For this study, we introduced mutated VirR boxes into a C. perfringens pfoA mutant and found that both VirR boxes are essential for transcriptional activation. Furthermore, the spacing between the VirR boxes and the distance between the VirR boxes and the −35 region are shown to be critical for perfringolysin O production. Other VirR boxes that were previously identified from the strain 13 genome sequence were also analyzed, with perfringolysin O production used as a reporter system. The results showed that placement of the different VirR boxes at the same position upstream of the pfoA promoter yields different levels of perfringolysin O activity. In all of these constructs, VirR was still capable of binding to the target DNA, indicating that DNA binding alone is not sufficient for transcriptional activation. Finally, we show that the C. perfringens RNA polymerase binds more efficiently to the pfoA promoter in the presence of VirR, indicating that interactions must occur between these proteins. We propose that these interactions are required for VirR-mediated transcriptional activation.

scholarly journals Cpx Two-Component Signal Transduction inEscherichia coli: Excessive CpxR-P Levels Underlie CpxA* Phenotypes

2000 ◽  
Vol 182 (5) ◽  
pp. 1423-1426 ◽  
Author(s):  
Peter De Wulf ◽  
E. C. C. Lin
Keyword(s):  
Signal Transduction ◽  
Response Regulator ◽  
Response Regulators ◽  
Signal Transduction System ◽  
Regulate Gene Expression ◽  
Adverse Conditions ◽  
Two Component ◽  
Sensor Protein ◽  
Two Component Signal Transduction ◽  
Cognate Response Regulator

ABSTRACT In Escherichia coli, the CpxA-CpxR two-component signal transduction system and the ςE and ς32response pathways jointly regulate gene expression in adaptation to adverse conditions. These include envelope protein distress, heat shock, oxidative stress, high pH, and entry into stationary phase. Certain mutant versions of the CpxA sensor protein (CpxA* proteins) exhibit an elevated ratio of kinase to phosphatase activity on CpxR, the cognate response regulator. As a result, CpxA* strains display numerous phenotypes, many of which cannot be easily related to currently known functions of the CpxA-CpxR pathway. It is unclear whether CpxA* phenotypes are caused solely by hyperphosphorylation of CpxR. We here report that all of the tested CpxA* phenotypes depend on elevated levels of CpxR-P and not on cross-signalling of CpxA* to noncognate response regulators.

scholarly journals Identifying potential novel insights for COVID-19 pathogenesis and therapeutics using an integrated bioinformatics analysis of host transcriptome

2021 ◽  
Author(s):  
Salem El-aarag ◽  
Amal Mahmoud ◽  
Mahmoud ElHefnawi
Keyword(s):  
Transcription Factors ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Hub Genes ◽  
Drug Candidates ◽  
Protein Protein Interaction ◽  
Target Network ◽  
Novel Drug

Abstract The molecular mechanisms underlying the pathogenesis of COVID-19 has not been fully discovered. This study aims to decipher potentially hidden parts of the pathogenesis of COVID-19, potential novel drug targets, and to identify potential drug candidates. Two gene expression profiles (GSE147507-GSE153970) were analyzed and overlapping differentially expressed genes (DEGs) were selected for which top enriched transcription factors and kinases were identified and pathway analysis was performed. Protein-protein interaction (PPI) of DEGs was constructed, hub genes were identified and module analysis was also performed. DGIdb database was used to identify drugs for the potential targets (hub genes and the most enriched transcription factors and kinases for DEGs). A drug-potential target network was constructed and drugs are ranked according to the degree. L1000FDW web-based utility was used to identify drugs that can reverse transcriptional profiles of COVID-19. We identified drugs currently in clinical trials and novel potential 8 drugs. Besides the well-known pathogenic pathways, It was found that axon guidance is a potential pathogenic pathway. Sema7A, which may exacerbate hypercytokinemia, is considered a potential novel drug target. Another potential novel pathway is related to TINF2 overexpression which may induce potential telomere dysfunction and hence DNA damage that may exacerbate lung fibrosis.

scholarly journals Omics Derived Biomarkers and Novel Drug Targets for Improved Intervention in Advanced Prostate Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 658
Author(s):  
Maria Frantzi ◽  
Marie C. Hupe ◽  
Axel S. Merseburger ◽  
Joost P. Schanstra ◽  
Harald Mischak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Survival Rates ◽  
Initial Therapy ◽  
Clinical Settings ◽  
Recommended Treatment ◽  
Novel Drug

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies, and the fifth leading cause of cancer related mortality in men. For advanced PCa, radical prostatectomy, radiotherapy, and/or long-term androgen deprivation therapy are the recommended treatment options. However, subsequent progression to metastatic disease after initial therapy results in low 5-year survival rates (29%). Omics technologies enable the acquisition of high-resolution large datasets that can provide insights into molecular mechanisms underlying PCa pathology. For the purpose of this article, a systematic literature search was conducted through the Web of Science Database to critically evaluate recent omics-driven studies that were performed towards: (a) Biomarker development and (b) characterization of novel molecular-based therapeutic targets. The results indicate that multiple omics-based biomarkers with prognostic and predictive value have been validated in the context of PCa, with several of those being also available for commercial use. At the same time, omics-driven potential drug targets have been investigated in pre-clinical settings and even in clinical trials, holding the promise for improved clinical management of advanced PCa, as part of personalized medicine pipelines.

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