scholarly journals The histidine kinase PdtaS is a cyclic di-GMP binding metabolic sensor that controls mycobacterial adaptation to nutrient deprivation

2019 ◽  
Author(s):  
Vignesh Narayan Hariharan ◽  
Chandrani Thakur ◽  
Albel Singh ◽  
Renu Gopinathan ◽  
Devendra Pratap Singh ◽  
...  
Keyword(s):  
Histidine Kinase ◽  
Systems Approach ◽  
Second Messengers ◽  
Cell Signalling ◽  
Two Component System ◽  
Regulatory Pathways ◽  
Transcriptional Dysregulation ◽  
Cyclic Diguanosine Monophosphate ◽  
Metabolic Sensor ◽  
Diguanosine Monophosphate

AbstractCell signalling relies on second messengers to transduce signals from the sensory apparatus to downstream components of the signalling pathway. In bacteria, one of the most important and ubiquitous second messengers is the small molecule cyclic diguanosine monophosphate (c-di-GMP). While the biosynthesis, degradation and regulatory pathways controlled by c-di-GMP are well characterized, the mechanisms through which c-di-GMP controls these processes is not completely understood. Here we present the first report of a c-di-GMP regulated sensor histidine kinase previously named PdtaS (Rv3220c), which binds to c-di-GMP at sub-micromolar concentrations, subsequently perturbing signalling of the PdtaS-PdtaR (Rv1626) two component system. Aided by biochemical analysis, molecular docking and structural modelling, we have characterized the binding site of c-di-GMP in the GAF domain of PdtaS. We show that a pdtaS knockout in M. smegmatis is severely compromised in growth on amino acid deficient media and exhibits global transcriptional dysregulation. Perturbation of the c-di-GMP-PdtaS-PdtaR axis results in a cascade of cellular changes recorded by a multi-parametric systems approach of transcriptomics, unbiased metabolomics and lipid analyses.One-sentence summaryThe universal bacterial second messenger cyclic di-GMP controls the mycobacterial nutrient stress response

scholarly journals Degradation of cyclic diguanosine monophosphate by a hybrid two-component protein protects Azoarcus sp. strain CIB from toluene toxicity

2016 ◽  
Vol 113 (46) ◽  
pp. 13174-13179 ◽  
Author(s):  
Zaira Martín-Moldes ◽  
Blas Blázquez ◽  
Claudine Baraquet ◽  
Caroline S. Harwood ◽  
María T. Zamarro ◽  
...  
Keyword(s):  
Aromatic Hydrocarbons ◽  
Response Regulator ◽  
Anaerobic Growth ◽  
Two Component System ◽  
Component System ◽  
Bacterial Physiology ◽  
Toxic Concentration ◽  
Two Component ◽  
Cyclic Diguanosine Monophosphate ◽  
Diguanosine Monophosphate

Cyclic diguanosine monophosphate (c-di-GMP) is a second messenger that controls diverse functions in bacteria, including transitions from planktonic to biofilm lifestyles, virulence, motility, and cell cycle. Here we describe TolR, a hybrid two-component system (HTCS), from the β-proteobacterium Azoarcus sp. strain CIB that degrades c-di-GMP in response to aromatic hydrocarbons, including toluene. This response protects cells from toluene toxicity during anaerobic growth. Whereas wild-type cells tolerated a sudden exposure to a toxic concentration of toluene, a tolR mutant strain or a strain overexpressing a diguanylate cyclase gene lost viability upon toluene shock. TolR comprises an N-terminal aromatic hydrocarbon-sensing Per–Arnt–Sim (PAS) domain, followed by an autokinase domain, a response regulator domain, and a C-terminal c-di-GMP phosphodiesterase (PDE) domain. Autophosphorylation of TolR in response to toluene exposure initiated an intramolecular phosphotransfer to the response regulator domain that resulted in c-di-GMP degradation. The TolR protein was engineered as a functional sensor histidine kinase (TolRSK) and an independent response regulator (TolRRR). This classic two-component system (CTCS) operated less efficiently than TolR, suggesting that TolR was evolved as a HTCS to optimize signal transduction. Our results suggest that TolR enables Azoarcus sp. CIB to adapt to toxic aromatic hydrocarbons under anaerobic conditions by modulating cellular levels of c-di-GMP. This is an additional role for c-di-GMP in bacterial physiology.

scholarly journals A Systems Approach Identifies Key Regulators of HPV-Positive Cervical Cancer

2020 ◽  
Author(s):  
Musalula Sinkala ◽  
Mildred Zulu ◽  
Panji Nkhoma ◽  
Doris Kafita ◽  
Ephraim Zulu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Regulatory Network ◽  
Drug Targets ◽  
Immune Cell ◽  
Systems Approach ◽  
Cell Signalling ◽  
Hpv Infection ◽  
Regulatory Pathways ◽  
Cervical Cancers ◽  
Functional Pathway

Cervical cancer has remained the most prevalent and lethal malignancy among women worldwide and accounted for over 250,000 deaths in 2019. Nearly ninety-five per cent of cervical cancer cases are associated with persistent infection with high-risk Human Papillomavirus (HPV), and seventy per cent of these are associated with viral integration in the host genome. HPV-infection imparts specific changes in the regulatory network of infected cancer cells that are of diagnostic, prognostic and therapeutic importance. Here, we conducted a systems-level analysis of the regulatory network changes, and the associated regulatory proteins thereof, in HPV-positive cervical cancer. We applied functional pathway analysis to show that HPV-positive cancers are characterised by perturbations of numerous cellular processes, predominantly in those linked to the cell cycle, mitosis, cytokine and immune cell signalling. Using computational predictions, we revealed that HPV-positive cervical cancers are regulated by transcription factors including, SOX2, E2F, NANOG, OCT4, and MYC, which control various processes such as the renewal of cancer stem cells, and the proliferation and differentiation of tumour cells. Through the analysis of upstream regulatory kinases, we identified the mitogen-activated protein kinases; among others, MAPK1, MAPK3 and MAPK8, and the cyclin-dependent kinases; among others, CDK1, CDK2 and CD4, as the key kinases that control the biological processes in HPV-positive cervical cancers. Taken together, we uncover a landscape of the key regulatory pathways and proteins in HPV-positive cervical cancers, all of which may provide attractive drug targets for future therapeutics.

scholarly journals Transcriptional regulation of metabolism in disease: From transcription factors to epigenetics

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5062 ◽  
Author(s):  
Liam J. Hawkins ◽  
Rasha Al-attar ◽  
Kenneth B. Storey
Keyword(s):  
Transcriptional Regulation ◽  
Genomic Sequence ◽  
Regulatory Elements ◽  
Regulatory Pathways ◽  
Transcriptional Dysregulation ◽  
Disease States ◽  
Specific Subset ◽  
Transcriptional Regulatory ◽  
Cis And Trans ◽  
Or Genes

Every cell in an individual has largely the same genomic sequence and yet cells in different tissues can present widely different phenotypes. This variation arises because each cell expresses a specific subset of genomic instructions. Control over which instructions, or genes, are expressed is largely controlled by transcriptional regulatory pathways. Each cell must assimilate a huge amount of environmental input, and thus it is of no surprise that transcription is regulated by many intertwining mechanisms. This large regulatory landscape means there are ample possibilities for problems to arise, which in a medical context means the development of disease states. Metabolism within the cell, and more broadly, affects and is affected by transcriptional regulation. Metabolism can therefore contribute to improper transcriptional programming, or pathogenic metabolism can be the result of transcriptional dysregulation. Here, we discuss the established and emerging mechanisms for controling transcription and how they affect metabolism in the context of pathogenesis. Cis- and trans-regulatory elements, microRNA and epigenetic mechanisms such as DNA and histone methylation, all have input into what genes are transcribed. Each has also been implicated in diseases such as metabolic syndrome, various forms of diabetes, and cancer. In this review, we discuss the current understanding of these areas and highlight some natural models that may inspire future therapeutics.

scholarly journals Cyclic Dinucleotide-Controlled Regulatory Pathways in Streptomyces Species

2015 ◽  
Vol 198 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Natalia Tschowri
Keyword(s):  
Cell Wall ◽  
Current Knowledge ◽  
Second Messengers ◽  
Streptomyces Species ◽  
Content Type ◽  
Regulatory Pathways ◽  
Cellular Processes ◽  
Signal Transduction Networks ◽  
Cyclic Dinucleotides ◽  
Cyclic Dinucleotide

The cyclic dinucleotides cyclic 3′,5′-diguanylate (c-di-GMP) and cyclic 3′,5′-diadenylate (c-di-AMP) have emerged as key components of bacterial signal transduction networks. These closely related second messengers follow the classical general principles of nucleotide signaling by integrating diverse signals into regulatory pathways that control cellular responses to changing environments. They impact distinct cellular processes, with c-di-GMP having an established role in promoting bacterial adhesion and inhibiting motility and c-di-AMP being involved in cell wall metabolism, potassium homeostasis, and DNA repair. The involvement of c-dinucleotides in the physiology of the filamentous, nonmotile streptomycetes remained obscure until recent discoveries showed that c-di-GMP controls the activity of the developmental master regulator BldD and that c-di-AMP determines the level of the resuscitation-promoting factor A(RpfA) cell wall-remodelling enzyme. Here, I summarize our current knowledge of c-dinucleotide signaling inStreptomycesspecies and highlight the important roles of c-di-GMP and c-di-AMP in the biology of these antibiotic-producing, multicellular bacteria.

scholarly journals Globins Synthesize the Second Messenger Bis-(3′–5′)-Cyclic Diguanosine Monophosphate in Bacteria

2009 ◽  
Vol 388 (2) ◽  
pp. 262-270 ◽  
Author(s):  
Xuehua Wan ◽  
Jason R. Tuckerman ◽  
Jennifer A. Saito ◽  
Tracey Allen K. Freitas ◽  
James S. Newhouse ◽  
...  
Keyword(s):  
Second Messenger ◽  
Cyclic Diguanosine Monophosphate ◽  
Diguanosine Monophosphate

scholarly journals Site-Directed Mutagenesis Identifies a Molecular Switch Involved in Copper Sensing by the Histidine Kinase CinS in Pseudomonas putida KT2440

2009 ◽  
Vol 191 (16) ◽  
pp. 5304-5311 ◽  
Author(s):  
Davide Quaranta ◽  
Megan M. McEvoy ◽  
Christopher Rensing
Keyword(s):  
Pseudomonas Putida ◽  
Histidine Kinase ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Copper Binding ◽  
Wild Type ◽  
Two Component System ◽  
Pseudomonas Putida Kt2440 ◽  
Component System ◽  
Two Component

ABSTRACT In the presence of copper, Pseudomonas putida activates transcription of cinAQ via the two-component system CinS-CinR. The CinS-CinR TCS was responsive to 0.5 μM copper and was specifically activated only by copper and silver. Modeling studies of CinS identified a potential copper binding site containing H37 and H147. CinS mutants with H37R and H147R mutations had an almost 10-fold reduced copper-dependent induction of cinAQ compared to the wild type.

scholarly journals Burkholderia cenocepacia integrates cis-2-dodecenoic acid and cyclic dimeric guanosine monophosphate signals to control virulence

2017 ◽  
Vol 114 (49) ◽  
pp. 13006-13011 ◽  
Author(s):  
Chunxi Yang ◽  
Chaoyu Cui ◽  
Qiumian Ye ◽  
Jinhong Kan ◽  
Shuna Fu ◽  
...  
Keyword(s):  
Guanosine Monophosphate ◽  
Burkholderia Cenocepacia ◽  
Gene Promoters ◽  
Biological Functions ◽  
Environmental Chemical ◽  
Cell Functions ◽  
Diffusible Signal Factor ◽  
Cyclic Diguanosine Monophosphate ◽  
Diguanosine Monophosphate ◽  
Physical And Chemical

Quorum sensing (QS) signals are used by bacteria to regulate biological functions in response to cell population densities. Cyclic diguanosine monophosphate (c-di-GMP) regulates cell functions in response to diverse environmental chemical and physical signals that bacteria perceive. In Burkholderia cenocepacia, the QS signal receptor RpfR degrades intracellular c-di-GMP when it senses the QS signal cis-2-dodecenoic acid, also called Burkholderia diffusible signal factor (BDSF), as a proxy for high cell density. However, it was unclear how this resulted in control of BDSF-regulated phenotypes. Here, we found that RpfR forms a complex with a regulator named GtrR (BCAL1536) to enhance its binding to target gene promoters under circumstances where the BDSF signal binds to RpfR to stimulate its c-di-GMP phosphodiesterase activity. In the absence of BDSF, c-di-GMP binds to the RpfR-GtrR complex and inhibits its ability to control gene expression. Mutations in rpfR and gtrR had overlapping effects on both the B. cenocepacia transcriptome and BDSF-regulated phenotypes, including motility, biofilm formation, and virulence. These results show that RpfR is a QS signal receptor that also functions as a c-di-GMP sensor. This protein thus allows B. cenocepacia to integrate information about its physical and chemical surroundings as well as its population density to control diverse biological functions including virulence. This type of QS system appears to be widely distributed in beta and gamma proteobacteria.

Integrated systems approach identifies risk regulatory pathways and key regulators in coronary artery disease

2015 ◽  
Vol 93 (12) ◽  
pp. 1381-1390 ◽  
Author(s):  
Yan Zhang ◽  
Dianming Liu ◽  
Lihong Wang ◽  
Shuyuan Wang ◽  
Xuexin Yu ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Systems Approach ◽  
Integrated Systems ◽  
Regulatory Pathways ◽  
Artery Disease

scholarly journals Assessing the Contributions of the LiaS Histidine Kinase to the Innate Resistance of Listeria monocytogenes to Nisin, Cephalosporins, and Disinfectants

2012 ◽  
Vol 78 (8) ◽  
pp. 2923-2929 ◽  
Author(s):  
Barry Collins ◽  
Caitriona M. Guinane ◽  
Paul D. Cotter ◽  
Colin Hill ◽  
R. Paul Ross
Keyword(s):  
Listeria Monocytogenes ◽  
Histidine Kinase ◽  
Fold Increase ◽  
Penicillin Binding Protein ◽  
Two Component System ◽  
Food Preservative ◽  
Content Type ◽  
Cephalosporin Resistance ◽  
Increased Sensitivity ◽  
Cephalosporin Antibiotics

ABSTRACTTheListeria monocytogenesLiaSR two-component system (2CS) encoded bylmo1021andlmo1022plays an important role in resistance to the food preservative nisin. A nonpolar deletion in the histidine kinase-encoding component (ΔliaS) resulted in a 4-fold increase in nisin resistance. In contrast, the ΔliaSstrain exhibited increased sensitivity to a number of cephalosporin antibiotics (and was also altered with respect to its response to a variety of other antimicrobials, including the active agents of a number of disinfectants). This pattern of increased nisin resistance and reduced cephalosporin resistance inL. monocytogeneshas previously been associated with mutation of a second histidine kinase, LisK, which is a predicted regulator ofliaSand a penicillin binding protein encoded bylmo2229. We noted thatlmo2229transcription is increased in the ΔliaSmutant and in a ΔliaSΔlisKdouble mutant and that disruption oflmo2229in the ΔliaSΔlisKmutant resulted in a dramatic sensitization to nisin but had a relatively minor impact on cephalosporin resistance. We anticipate that further efforts to unravel the complex mechanisms by which LiaSR impacts on the antimicrobial resistance ofL. monocytogenescould facilitate the development of strategies to increase the susceptibility of the pathogen to these agents.

Sign in / Sign up

Export Citation Format

Share Document