Repression of the RcsC‐YojN‐RcsB phosphorelay by the IgaA protein is a requisite for <i>Salmonella</i> virulence

Domínguez‐Bernal, Gustavo; Pucciarelli, M. Graciela; Ramos‐Morales, Francisco; García-Quintanilla, Meritxell; Cano, David A.; Casadesús, Josep; Portillo, Francisco García‐del

doi:10.1111/j.1365-2958.2004.04213.x

Cited by 87 publications

(164 citation statements)

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“…Spontaneous mutations consisting of deletions leading to a diminished production of RcsC or RcsD are also known to suppress IgaA essentiality (42). Important traits of serovar Typhimurium, such as its virulence potential, depend on the fine-tuning of the activity of the RcsCDB system (17,28,45). IgaA and the RcsCDB system are present in the same genera of enteric bacteria (17,20,34), and this concurrence strongly supports the functional link existing between IgaA and the RcsCDB system.…”

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confidence: 80%

“…In serovar Typhimurium, 26 RcsB-dependent but RcsA-independent genes were reported upon exposure of bacteria to sublethal concentrations of antimicrobial peptides (20). Recent studies performed with serovar Typhimurium expressing IgaA(T191P), a variant previously shown by us to be unable to repress the RcsCDB system (17), revealed that one-fifth of the genes analyzed displayed expression changes higher than twofold (55).…”

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confidence: 99%

“…Activation of the RcsCDB system in E. coli has been correlated in most cases to envelope stress (34,39). However, mutations in IgaA causing partial loss of function (igaA1 allele) do not alter envelope integrity in serovar Typhimurium (17,42). Thus, activation of the RcsCDB system does not necessarily impair envelope homeostasis, and some remodeling may be tolerable without compromising basic envelope functions.…”

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confidence: 99%

“…We also investigated the Rcs regulon in strains producing an IgaA(R188H) variant (R188H is the first mutation characterized for this attenuator to cause overactivation of the RcsCDB system [6,7,17,27,54]) and in recently described IgaA-deficient strains having reduced RcsC or RcsD levels (42). The study has provided new insights into the mode of attenuation exerted by IgaA on the RcsCDB system and has led to the first evidence supporting a role for dephosphorylated RcsB as a transcriptional regulator.…”

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Genome Expression Analyses Revealing the Modulation of the Salmonella Rcs Regulon by the Attenuator IgaA

Mariscotti

Portillo

2009

J Bacteriol

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Intracellular growth attenuator A (IgaA) was identified as a Salmonella enterica regulator limiting bacterial growth inside fibroblasts. Genetic evidence further linked IgaA to repression of the RcsCDB regulatory system, which responds to envelope stress. How IgaA attenuates this system is unknown. Here, we present genome expression profiling data of S. enterica serovar Typhimurium igaA mutants grown at high osmolarity and displaying exacerbated Rcs responses. Transcriptome data revealed that IgaA attenuates gene expression changes requiring phosphorylated RcsB (RcsBϳP) activity. Some RcsB-regulated genes, yciGFE and STM1862 (pagO)-STM1863-STM1864, were equally expressed in wild-type and igaA strains, suggesting a maximal expression at low levels of RcsBϳP. Other genes, such as metB, ypeC, ygaC, glnK, glnP, napA, glpA, and nirB, were shown for the first time and by independent methods to be regulated by the RcsCDB system. Interestingly, IgaA-deficient strains with reduced RcsC or RcsD levels exhibited different Rcs responses and distinct virulence properties. spv virulence genes were differentially expressed in most of the analyzed strains. spvA expression required RcsB and IgaA but, unexpectedly, was also impaired upon stimulation of the RcsC3 RcsD3RcsB phosphorelay. Overproduction of either RcsB ؉ or a nonphosphorylatable RcsB(D56Q) variant in strains displaying low spvA expression unveiled that both dephosphorylated RcsB and RcsBϳP are required for optimal spvA expression. Taken together, our data support a model with IgaA attenuating the RcsCDB system by favoring the switch of RcsBϳP to the dephosphorylated state. This role of IgaA in constantly fine-tuning the RcsBϳP/RcsB ratio may ensure the proper expression of important virulence factors, such as the Spv proteins.

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confidence: 99%

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confidence: 99%

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Genome Expression Analyses Revealing the Modulation of the Salmonella Rcs Regulon by the Attenuator IgaA

Mariscotti

Portillo

2009

J Bacteriol

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“…There is another cytoplasmic membrane protein YrfF likely to regulate the system negatively: its homolog in Salmonella enterica, IgaA, was reported to repress the Rcs activity (Cano et al, 2002). The repression by Salmonella IgaA is crucial for the virulence of this intracellular pathogen (Domínguez-Bernal et al, 2004). In Legionella dumoffii DjlA is required for intracellular growth (Ohnishi et al, 2004), which may be because of its negative regulatory function on the Rcs system.…”

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DjlA negatively regulates the Rcs signal transduction system in Escherichia coli

2006

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The Rcs signal transduction system of Escherichia coli regulating capsular polysaccharide synthesis ( cps ) genes is activated by overexpression of the djlA gene encoding a cytoplasmic membrane-anchored DnaJ-like protein. However, by monitoring the expression of a cpsB '-lac fusion in pgsA -and mdoH -null mutants in which the Rcs system is activated, we found that the Rcs activity was further increased by deletion of djlA and decreased by low-level extrachromosomal expression of djlA . Furthermore, deletion of djlA in a wild-type strain led to small but significant increase of the basal-level activity of the Rcs system. These results demonstrate that DjlA functions as a negative regulator of the Rcs system unless abnormally overproduced.

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Regulatory Systems: Two‐Component

Raivio

2019

Encyclopedia of Life Sciences

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Two‐component signal transduction (TCST) systems constitute a large class of regulatory proteins that function as signal transducers. Each system comprises a sensor or histidine kinase (HK) and an effector or response regulator (RR), which communicate through a conserved set of phosphotransfer reactions to effect adaptive changes in response to specific environmental signals. HKs and RRs are modular in nature, with variable sensory and output structures appended to the conserved domains that facilitate phosphotransfer mediated signal transduction. Input signals trigger successive conformational changes in domains and protein:protein interactions that alter phosphotransfer, and ultimately an output response mediated by the phosphorylated RR. TCST systems are abundant in bacteria and many microbes utilise multiple TCST pathways to sense and respond to a plethora of environmental and physiological changes. Specificity between cognate HKs and RRs is largely maintained through co‐evolving residues at a conserved interface where the RR docks on the HK. TCST systems are integrated into cellular signalling networks and interact with macromolecules and proteins that connect them to salient regulatory pathways and cellular functions. The current state of knowledge around TCST systems will be summarised, emphasising findings published since the first version of this article in 2006. Key Concepts A prototypical two‐component system is made up of a membrane‐bound sensory histidine kinase that senses a unique environmental or cellular parameter and a cytoplasmic response regulator that controls an adaptive response. HKs and RRs communicate through phosphotransfer reactions that are mediated by conserved domains; signal sensing alters the ratio of HK kinase to phosphatase activity to change the function of the RR by altering its phosphorylation status. HKs and RRs are organised in a modular fashion; a variety of sensing domains can be appended to the HK enzymatic module while diverse output domains with DNA binding, RNA binding, enzymatic activity or protein binding functions are often fused to the C‐terminal end of the response regulator phosphorylated receiver (REC) domain. The HK is a dimer containing a catalytic domain composed of two DHp and CA domains. The DHp domain consists of a d imer of two alpha helices connected by a flexible linker that makes a four‐helical bundle and contains the conserved h istidine that is the site of auto p hosphorylation. The CA domain resembles other ATP‐binding folds and is the enzymatic portion of the HK. The RR consists at its N‐terminus of the conserved receiver (REC) domain, which consists of a five‐stranded beta sheet surrounded by alpha helices and contains the conserved aspartate that is the site of phosphorylation. Signals are detected through conformational changes in a sensory domain that are propagated through some combination of rotational, piston and order to disorder transitions by alpha‐helical transduction elements to the cytoplasmic enzymatic domain of the HK. These movements lead to alterations in HK dimer symmetry that dictate kinase or phosphatase activity. In the inactive state, the cytoplasmic DHp and CA domains of the HK are organised in a symmetrical fashion with the CA domain juxtaposed against the membrane‐proximal end of the DHp four‐helical bundle. The RR REC domain can interact with the inactive HK DHp four‐helical bundle at a more membrane‐distal location in an orientation that would facilitate dephosphorylation of the aspartate. The active, kinase state of the HK is asymmetrical due to a bend or kink in the DHp domain that leads to one CA domain adopting a looser association that positions it well for phosphorylation of a histidine residue. A single RR REC domain can bind near the other CA domain, which is more closely associated with the DHp domain, in a conformation supporting phosphorylation of the aspartate residue utilising the phosphorylated histidine as a substrate. Repeated cycles of DHp domain bending and RR REC domain binding are hypothesised to support successive rounds of HK autophosphorylation and RR phosphorylation in response to signal inputs received from the sensory domain. HKs and RRs regulate and interact with other macromolecules and proteins to connect signalling pathways, coordinate their activities and sense environmental parameters and changes to cellular physiology.

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Repression of the RcsC‐YojN‐RcsB phosphorelay by the IgaA protein is a requisite for Salmonella virulence

Cited by 87 publications

References 49 publications

Genome Expression Analyses Revealing the Modulation of the Salmonella Rcs Regulon by the Attenuator IgaA

Genome Expression Analyses Revealing the Modulation of the Salmonella Rcs Regulon by the Attenuator IgaA

DjlA negatively regulates the Rcs signal transduction system in Escherichia coli

Regulatory Systems: Two‐Component

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