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A thorough understanding of the mechanisms that allow bacteria to thrive in various environments is crucial to the development of new antibiotics, an urgent endeavor to combat antimicrobial resistance. A landmark feature of Gram-negative bacteria is the presence of a multi-layered envelope. Because this structure is essential, its in...
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... IgaA MalF -fl was able to fully rescue the growth of the depletion strain under non-permissive conditions (Fig 4A) and repressed Rcs activation to a level similar to that observed when wild-type IgaA was expressed (Fig 4B). Consistent with this, cells expressing IgaA MalF -fl remained viable after igaA deletion, only exhibiting a mild growth defect (Table 1). Thus, altogether, these data indicated that the inhibitory activity exerted by IgaA on the Rcs system does not depend on the periplasmic domain but rather on the cytoplasmic and membranous regions. ...
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... significant, the impact of expressing IgaA cyt1-cyt2 -fl or IgaA cyt1 -fl on Rcs repression was, however, only partial (Fig 4B). Consistent with this, expression of these two IgaA variants did not allow igaA to be deleted from the chromosome ( Table 1). This led us to investigate the importance of anchoring the cytoplasmic domains of IgaA to the membrane. ...
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... expression of IgaA 1-370 -fl did not substantially improve survival of the depletion strain compared to IgaA cyt1-cyt2 -fl or IgaA cyt1 -fl (Fig 4A). It also did not have a signif- icant impact on Rcs repression compared to the cytosolic domains alone (Fig 4B) and did not allow the igaA::kan allele to be transduced (Table 1). Thus, anchoring the cytoplasmic domains to the membrane does not significantly increase their ability to repress Rcs. ...
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... led us to investigate whether full IgaA inhibitory activity could be recovered by co-expressing its N-and C-terminal portions. Excitingly, we found that co-expression of IgaA 1-370 -fl and IgaA 324-711 -His allowed deletion of the chromosomal copy of igaA ( Table 1) and fully repressed Rcs (Fig 5). Thus, although the N-terminal domain of IgaA is crucially important for tuning down Rcs, complete inhibition can only be achieved when the C-termi- nal domain is co-expressed (see Discussion). ...
Citations
... The thiol oxidase DsbA probably provides feedback control to the CpxR/A system, because its coding gene is part of the Cpx regulon in E. coli, but also in Salmonella and other bacteria (86)(87)(88). Similarly, activation by redox stress of the Rcs system, a phospho-relay also contributing to envelope homeostasis, involves two proteins exposing Cys to the periplasm, the OM lipoprotein RcsF and the IM system repressor IgaA (89)(90)(91)(92)(93). RcsF usually remains in the OM trapped in a complex with BAM, the protein incorporation β-barrel assembly machinery, and porins. ...
The bacterial envelope is an essential compartment involved in metabolism and metabolites transport, virulence, and stress defense. Its roles become more evident when homeostasis is challenged during host–pathogen interactions. In particular, the presence of free radical groups and excess copper in the periplasm causes noxious reactions, such as sulfhydryl group oxidation leading to enzymatic inactivation and protein denaturation. In response to this, canonical and accessory oxidoreductase systems are induced, performing quality control of thiol groups, and therefore contributing to restoring homeostasis and preserving survival under these conditions. Here, we examine recent advances in the characterization of the Dsb-like, Salmonella-specific Scs system. This system includes the ScsC/ScsB pair of Cu⁺-binding proteins with thiol-oxidoreductase activity, an alternative ScsB-partner, the membrane-linked ScsD, and a likely associated protein, ScsA, with a role in peroxide resistance. We discuss the acquisition of the scsABCD locus and its integration into a global regulatory pathway directing envelope response to Cu stress during the evolution of pathogens that also harbor the canonical Dsb systems. The evidence suggests that the canonical Dsb systems cannot satisfy the extra demands that the host-pathogen interface imposes to preserve functional thiol groups. This resulted in the acquisition of the Scs system by Salmonella. We propose that the ScsABCD complex evolved to connect Cu and redox stress responses in this pathogen as well as in other bacterial pathogens.
... The bacterial strains used in this study are all derivatives of E. coli K12 MG1655 carrying a chromosomal rprA::lacZ fusion at the lambda attachment site (DH300) (Majdalani et al. 2002). This strain was used previously as a reporter strain to monitor the Rcs system activation in the absence and presence of Rcs-specific inducing cues (Cho et al. 2014;Asmar et al. 2017;Hussein et al. 2018;Lach et al. 2023). The rcsB and rcsF knockout strains were generated by P1 vir transduction from the corresponding Keio collection strain (Baba et al. 2006) (obtained from the National Bioresource Project, Japan) to E. coli MG1655 DH300 and were checked by corresponding PCR primers complementary to the upstream and downstream genomic locus of each gene. ...
... Whenever required, isopropyl β-thiogalactoside (IPTG) was added at a final concentration of 100 µM, L-arabinose and D-fucose at a final concentration of 0.2% weight/ volume. Plasmids used in this study are all derived from either pSC232 or pNH401 previously described in (Hussein et al. 2018). pSC232 is derived from pSC101 (Dominique and Bouché 1991), modified by inserting lacIq and trc promoter from pTrc99a plasmid and is a kind gift from Dr Seun-Hyun Cho, Collet lab. ...
... pSC232 is derived from pSC101 (Dominique and Bouché 1991), modified by inserting lacIq and trc promoter from pTrc99a plasmid and is a kind gift from Dr Seun-Hyun Cho, Collet lab. pNH401 is derived from the L-arabinose inducible pBAD33 (Guzman et al. 1995) as described in (Hussein et al. 2018). rcsFmim nucleotide sequence was synthesized as gene block by IDT (Belgium) and was cloned between NcoI and XbaI restriction sites in pSC232 or SacI Fig. 1 Schematic diagram of RcsF interactions and role in the activation of the Rcs system. ...
Escherichia coli cell envelope is crucial for stress sensing and signal transduction, mediated by numerous protein–protein interactions to enable adaptation and survival. Interfering with these interactions might affect envelope integrity leading to bacterial death. The outer membrane lipoprotein (RcsF) is the stress sensor of the regulator of capsule synthesis (Rcs) phosphorelay that senses envelope threats. RcsF interacts with two essential proteins, IgaA (repressing the Rcs system) and BamA (inserting β-barrel proteins in the outer membrane). Disturbing RcsF interactions may alter Rcs signaling and/or membrane integrity thus affecting bacterial survival. Here, we derived the sequence of a peptide mimicking RcsF (RcsFmim), based on the in silico docking of RcsF with IgaA. Expression of rcsF mim caused 3-to-4-fold activation of the Rcs system and perturbation of the outer membrane. Both effects result in decreased E. coli growth rate. We anticipate that RcsFmim present a candidate for future antibacterial peptide development.
... Typhimurium) and Escherichia coli have provided compelling evidence for a tight control of the Rcs system under non-stress conditions. This control impedes unnecessary activation, which has been shown to be detrimental for viability [3][4][5][6][7]. ...
... An interaction between the outer membrane protein RcsF and the periplasmic region of IgaA was proposed to relieve its repression over RcsC/RcsD [10]. More recent studies have reported interactions between outer membrane proteins and RcsF, modulating the RcsF-IgaA interaction [11,12], and, between RcsD and IgaA [6,7], this latter involving periplasmic and cytoplasmic domains [7]. ...
... Ortholog members of the IgaA family characterized to date include UmoB of Proteus miriabilis [9] and GumB of Serratia marcenses [13]. In contrast to S. Typhimurium and E. coli [3,[5][6][7], the lack of the IgaA orthologs UmoB and GumB does not compromise viability in P. mirabilis or S. marcenses [9,13]. These findings indicate that, although conserving its master role as repressor of the Rcs system, IgaA may have evolved differently within the Enterobacterales order. ...
The Rcs sensor system, comprising the RcsB/RcsC/RcsD and RcsF proteins, is used by bacteria of the order Enterobacterales to withstand envelope damage. In non-stress conditions, Rcs is repressed by IgaA, a membrane protein with three cytoplasmic regions (cyt-1, cyt-2 and cyt-3). How the Rcs-IgaA axis evolved within Enterobacterales has not been yet explored. Here, we report phylogenetic data supporting co-evolution of IgaA with RcsC/RcsD. Functional exchange assays showed that IgaA from Shigella and Dickeya, but not from Yersinia or the endosymbionts Photorhabdus and Sodalis, repress the Rcs system of Salmonella. IgaA from Dickeya, however, repress only partially the Rcs system despite being produced at high levels in the complementation assay. The modelled structures of these IgaA variants uncovered one periplasmic and two cytoplasmic conserved β-rich architectures forming partially closed small β-barrel (SBB) domains. Conserved residues map in a connector linking cytoplasmic SSB-1 and SBB-2 domains (E180-R265); a region of cyt-1 facing cyt-2 (R188-E194-D309 and T191-H326); and between cyt-2 and cyt-3 (H293-E328-R686). These structures validated early in vivo studies in Salmonella that assigned a role in function to R188, T191 and G262, and in addition revealed a previously unnoticed “hybrid” SBB-2 domain to which cyt-1 and cyt-2 contribute. IgaA variants not functional or partially functional in Salmonella lack H192-P249 and R255-D313 interactions. Among these variants, only IgaA from Dickeya conserves the helix α6 in SSB-1 that is present in IgaA from Salmonella and Shigella. RcsF and RcsD, which interact directly with IgaA, failed to show structural features linked to specific IgaA variants. Altogether, our data provide new insights into IgaA by mapping residues selected differently during evolution and involved in function. Our data also infer contrasting lifestyles of Enterobacterales bacteria as source of variability in the IgaA-RcsD/IgaA-RcsF interactions.
... RcsF is an OM lipoprotein with a long flexible linker domain at the N-terminus and a C-terminal globular domain (Leverrier et al., 2011;Rogov et al., 2011;Umekawa et al., 2013). The C-terminal domain (CTD) interacts directly with the negative regulator, IgaA, to relieve Rcs repression in stress conditions ( Fig. 2A) (Cho et al., 2014;Hussein et al., 2018). In E. coli, the OM and PG are covalently connected by the most abundant protein, Lpp, which forms an α-helical trimer with coiled-coiled motifs and a rigid pillar-like structure dictating a relatively constant height between the OM and PG (Asmar & Collet, 2018;Braun & Rehn, 1969). ...
The global public health burden of bacterial antimicrobial resistance (AMR) is intensified by Gram-negative bacteria, which have an additional membrane, the outer membrane (OM), outside of the peptidoglycan (PG) cell wall. Bacterial two-component systems (TCSs) aid in maintaining envelope integrity through a phosphorylation cascade by controlling gene expression through sensor kinases and response regulators. In Escherichia coli, the major TCSs defending cells from envelope stress and adaptation are Rcs and Cpx, which are aided by OM lipoproteins RcsF and NlpE as sensors, respectively. In this review, we focus on these two OM sensors. β-Barrel assembly machinery (BAM) inserts transmembrane OM proteins (OMPs) into the OM. BAM co-assembles RcsF, the Rcs sensor, with OMPs, forming the RcsF-OMP complex. Researchers have presented two models for stress sensing in the Rcs pathway. The first model suggests that LPS perturbation stress disassembles the RcsF-OMP complex, freeing RcsF to activate Rcs. The second model proposes that BAM cannot assemble RcsF into OMPs when the OM or PG is under specific stresses, and thus, the unassembled RcsF activates Rcs. These two models may not be mutually exclusive. Here, we evaluate these two models critically in order to elucidate the stress sensing mechanism. NlpE, the Cpx sensor, has an N-terminal (NTD) and a C-terminal domain (CTD). A defect in lipoprotein trafficking results in NlpE retention in the inner membrane, provoking the Cpx response. Signaling requires the NlpE NTD, but not the NlpE CTD; however, OM-anchored NlpE senses adherence to a hydrophobic surface, with the NlpE CTD playing a key role in this function.
... Регуляторная активность Rcs включает гены, ответственные за синтез колановой кислоты, повышение кислотоустойчивости, регулирующие деление клеток и подвижность, а также образование биопленок. Система Rcs функционирует как глобальный регулятор, контролирующий состав клеточной поверхности в ответ на изменение окружающей среды [22,23]. В состав Rcs-комплекса входят липопротеин внешней мембраны RcsF и основной белок внутренней мембраны IgaA (аттенюатор), а также четыре отдельных белка: RcsA, RcsB, RcsC и RcsD. ...
In the laboratory of metagenome analysis there were obtained Escherichia coli BW25113 mutants resistant to infection with the T7 phage and possessing a mucoid phenotype. Tasks were set in carrying out whole genome sequencing of mutants and their further bioinformatic processing on the basis of bioinformatic analysis in order to determine the mechanism of acquiring resistance to bacteriophages. Bioinformatic analysis included searching genome variants for the strains under investigation by Bowtie2 and SNP calling software, prediction the importance of genome variants by IGV-browser, and predicting functions of the variants by the use of EcoCyc and NCBI open databases. As a result, mutations in the locus of genes igaA, RcsC, yjbF, yjbG, and yjbH affecting the components of the Rcs signal transmission cascade, the main regulator of the expression of the yjbEFGH gene cluster, responsible for the synthesis of colanic acid, were detected taking into account the results of previous research. Thus, it was proved that the discovered resistance arose during the selection of mutants forming a colane capsule that prevents the adsorption of phage particles by creating a physical barrier in front of the phage receptor on the cell surface. Genetic screenings adjusted to new combinations of phage attacks on bacteria are of great importance to get an insight into the ways of phages’ and phenotypes’ infecting and resistance genotypes. Currently, the insight into the reasons of bacteria resistance to phages is insufficient, therefore, the paper is aimed at filling the gap.
... This control impedes unnecessary activation, which has been shown to be detrimental for viability. [3][4][5][6][7] An important element in the control of the Rcs system is the negative regulator IgaA, an essential inner membrane protein identified in S. Typhimurium as a factor that reduces the growth rate of this pathogen following the entry into eukaryotic cells. 3,8 Previously, an IgaA ortholog of Proteus mirabilis named UmoB, was shown to control flagellar synthesis and swarming 9 , functions controlled by the Rcs system. ...
... 1,2 Ortholog members of the IgaA family characterized to date include UmoB of Proteus miriabilis 9 and GumB of Serratia marcenses. 12 In contrast to S. Typhimurium and E. coli, 3,[5][6][7] the lack of the IgaA orthologs UmoB and GumB does not compromise viability in P. mirabilis or S. marcenses. 9,12 These findings indicate that, although conserving its master role as repressor of the Rcs system, IgaA may have evolved differently within the Enterobacterales order. ...
... In the context of that study and our analyses, it can be hypothesized that the three SBB domains act in concert to transduce signal from the periplasm to the cytoplasm, being the basis of the mechanism by which IgaA could repress the Rcs system. The essential role played by the cytoplasmic regions of IgaA, as pointed by Wall et al. 7 and further inferred from our study, also agrees with the data of Hussein et al. 6 Despite restoring viability in E. coli transiently depleted of IgaA but expressing IgaA cyt1 and cyt2 fragments, these authors were unable to complement a DigaA::Km null allele with the individual fragments. 6 The most accepted model of communication between IgaA and the Rcs system is a control at the periplasmic side exerted by an IgaA-RcsF interaction, 10 which is relieved upon stress, an alteration that is supposed to be translated to cytoplasmic regions of IgaA. ...
The Rcs sensor system, comprised by the proteins RcsB/RcsC/RcsD and RcsF, is used by bacteria of the order Enterobacterales to withstand envelope damage. Under non-stress conditions, the system is repressed by the membrane protein IgaA. How IgaA has evolved within Enterobacterales in concert with the Rcs system has not been explored. Here, we report phylogenetic data supporting co-evolution of IgaA with the inner membrane proteins RcsC and RcsD. Functional assays showed that IgaA from representative genera as Shigella and Dickeya , but not those from Yersinia or the endosymbionts Photorhabdus and Sodalis , repress the Rcs system when expressed in a heterogenous host like Salmonella enterica serovar Typhimurium. IgaA structural features have therefore diverged among Enterobacterales . Modelling of IgaA structure unveiled one periplasmic and two cytoplasmic β-rich architectures forming partially-closed small β-barrel (SBB) domains related to OB (oligonucleotide/oligosaccharide binding motif) fold domains. Interactions among conserved residues were mapped in a connector linking SBB-1 domain of cytoplasmic region cyt1 to SBB-2 domain of region cyt2 (residues E180-R265); the C-terminus of cyt1 facing cyt2 (R188-E194-D309 and T191-H326); and, between cyt2-cyt3 regions (H293-E328-R686). These interactions identify a previously unnoticed "hybrid" SBB-2 domain. We also identified interactions absent in the IgaA variants not functional in S. Typhimurium, including H192-P249, which links cyt1 to cyt2, R255-D313 and D287-R314. A short α-helix (α6) located in the SSB-1 domain is also missing in the non-complementing IgaA tested. Taken together, our data support a central role of the two cytoplasmic SBB domains in IgaA function and evolution.
SIGNIFICANCE
The "intracellular growth attenuator A" protein (IgaA) was first reported as repressor of the Rcs system in S. enterica serovar Typhimurium. IgaA orthologs were later studied in other genera and families of the Enterobacterales order, mainly in Escherichia coli . Despite intense investigation about the mechanism by which IgaA controls the Rcs system, the extent at which IgaA evolved within families of the Enterobacterales order has not been investigated. Using a combination of functional assays and in silico structural analyses, our work provides a detail map of conserved and divergent residues in IgaA representing interactions occurring in all Enterobacterales and others that may have diverged concomitantly to interacting proteins, probably for responding to specific environments. Future studies involving mutagenesis of these residues in IgaA of Enterobacterales families and genera of interest will certainly provide valuable insights into the regulation acting in the IgaA-Rcs axis.
... IgaA is a polytopic IM protein with a large periplasmic domain, and it inhibits the phosphorelay through RcsD (7,8). The OM lipoprotein RcsF is a sensory component of the Rcs cascade, which activates downstream signaling in response to stress by releasing IgaA inhibition (8)(9)(10)(11)(12). However, sensing by RcsF and signal transduction to IgaA are poorly understood at a molecular level, in part because many distinct genetic and chemical stimuli can induce Rcs, including defects in lipoprotein biogenesis (13)(14)(15), cell wall biogenesis (12,(16)(17)(18)(19), and the defects of LPS at the cell surface (as a result of Polymyxin B [PMB] treatment, for example) (19)(20)(21)(22). ...
... To examine the RcsF/ BamA interaction interface in bamE+ and ΔbamE backgrounds, we used site-specific cross-linking based on incorporation of photoactivatable p-Benzoylphenylalanine (pBPA) using amber suppression (36). We previously reported that RcsF/BamA crosslinking sites were limited to the distal tip of the RcsF CTD (11). We rebuilt the rcsF amber mutant library into the low-copy number vector pZS21 to avoid overexpression and probed the RcsF/BamA interaction in the wild-type (WT) and ΔbamE strains (Fig. 2). ...
... LPS stress is detected by the surface-exposed RcsF NTD, leading to a conformational change in the RcsF/ OMP complex and signal transmission to the periplasmic CTD ( Fig. 1A) (19,23). The RcsF CTD activates the downstream signaling by interacting with the large periplasmic domain of IgaA, releasing the inhibition of phosphorelay (7,11,12). ...
Significance
The bacterial cell envelope is the frontline defense against host immune factors and antibiotics. The regulator of capsule synthesis (Rcs) is a complex signaling pathway that maintains the homeostasis of this essential organelle. Several hypotheses for how the sensory component RcsF activates signaling in response to stress were proposed but could not be directly tested because RcsF proper assembly into the complex with outer membrane proteins (OMPs) depends on the essential β-barrel assembly machine (Bam). We used an extensive genetic analysis to tease apart which RcsF interactions are important for the sensing function. We show that RcsF does not monitor the Bam complex function. Instead, the Bam complex is required to assemble the sensory RcsF/OMP complex that monitors membrane integrity.
... A recent report demonstrated direct interactions between RcsD and IgaA, and it appears that a primary role of IgaA is to inhibit signaling from RcsC through RcsD (29). Therefore, it seems likely that the A564P mutation may weaken its association with either RcsF or RcsD because this mutation resides in the large periplasmic domain of IgaA (78). ...
By evolving strains of E. coli that hyper-resist sedimentation, we discovered an uncharacterized mechanism that bacteria can use to remain in suspension indefinitely without expending energy. This unusual phenotype was traced to the anchoring of long colanic acid polymers (CAP) that project from the cell surface. Although each characterized mutant activated this same mechanism, the genes responsible and the strengths of the phenotypes varied. Mutations in rcsC , lpp , igaA, or the yjbEFGH operon were sufficient to stimulate sedimentation resistance, while mutations altering the cps promoter, cdgI, or yjbF provided phenotypic enhancements. The sedimentation resistances changed in response to temperature, growth phase, and carbon source and each mutant exhibited significantly reduced biofilm formation. We discovered that the degree of colony mucoidy exhibited by these mutants was not related to the degree of Rcs pathways activation or to the amount of CAP that was produced; rather, it was related to the fraction of CAP that was shed as a true exopolysaccharide. Therefore, these and other mutations that activate this phenotype are likely to be absent from genetic screens that relied on centrifugation to harvest bacteria. We also found that this anchored CAP form is not linked to LPS cores and may not be attached to the outer membrane.
IMPORTANCE
Bacteria can partition in aqueous environments between surface-dwelling, planktonic, sedimentary, and biofilm forms. Residence in each location provides an advantage depending on nutritional and environmental stresses and a community of a single species is often observed to be distributed throughout two or more of these niches. Another adaptive strategy is to produce an extracellular capsule, which provides an environmental shield for the microbe and can allow escape from predators and immune systems. We discovered that bacteria can either shed or stably anchor capsules to dramatically alter their propensity to sediment. The degree to which the bacteria anchor their capsule is controlled by a stress sensing system, suggesting that anchoring may be used as an adaptive response to severe environmental challenges.
... Given the crucial function played by many outer membrane lipoproteins, bacteria have evolved molecular systems to monitor their trafficking across the cell envelope. In E. coli, failure to target outer membrane lipoproteins to their final destination triggers two envelope stress responses, Rcs and Cpx [77][78][79][80][81]. While Rcs copes with outer membrane and peptidoglycan defects [82 ], Cpx responds to a broad range of perturbations, including protein misfolding and inner membrane stress [83]. ...
... Both Rcs and Cpx can be triggered by an outer membrane lipoprotein, RcsF and NlpE, respectively [8]. When perturbations occur in lipoprotein trafficking, RcsF and NlpE accumulate in the inner membrane, where they can reach their downstream partner (IgaA for RcsF [80,81] and CpxA for NlpE [78,79]), thereby activating their respective signaling cascade. Although Rcs activation leads to higher lolA expression [84], which should help fix the damage, it does not provide a fitness advantage when trafficking is perturbed, in contrast to Cpx activation which is beneficial to mutants with defective lipoprotein biogenesis [77][78][79]]. ...
... This structure suggests a push-and-pull mechanism for the transfer of RcsF to its b-barrel partners [101 ] and provides a molecular explanation to the observation that RcsF accumulation on BamA lethally blocks b-barrel assembly [102 ,103 ]. Interestingly, RcsF uses its interaction with BamA to detect stress in the cell envelope: when damage occurs in the peptidoglycan or the outer membrane, newly synthesized RcsF molecules fail to interact with BamA, they are not exported to the surface and remain exposed to the periplasm, which allows them to trigger the Rcs signaling cascade by reaching IgaA [80,81]. ...
Bacterial lipoproteins are globular proteins anchored to a membrane by a lipid moiety. By discovering new functions carried out by lipoproteins, recent research has highlighted the crucial roles played by these proteins in the cell envelope of Gram-negative bacteria. Here, after discussing the wide range of activities carried out by lipoproteins in the model bacterium Escherichia coli, we review new insights into the essential mechanisms involved in lipoprotein maturation, sorting and targeting to their final destination. A special attention will also be given to the recent identification of lipoproteins on the surface of E. coli and of other bacteria. The renewed interest in lipoproteins is driven by the need to identify novel targets for antibiotic development.
... The cell envelope of Gram-negative bacteria is composed of an OM that is separated from the IM by an aqueous periplasmic space that houses the peptidoglycan cell wall, thereby acting as a protective barrier at the frontline of the interaction between bacteria and the environment. Danese and Silhavy, 1998;Otto and Silhavy, 2002;Jubelin et al., 2005;Yamamoto and Ishihama, 2006;Evans et al., 2013;López et al., 2018;Delhaye et al., 2019;May et al., 2019 Bae system Toxic molecules Upon receiving a stimulus, the BaeS autophosphorylates at its HK domain, and the phosphoryl group is transferred to the PR domain of the response regulator BaeR to activate the Bae system Periplasmic chaperone; efflux Nagakubo et al., 2002;Raffa and Raivio, 2002;Zhou et al., 2003;Nishino et al., 2005;Bury-Moné et al., 2009;Leblanc et al., 2011 Psp system Severe damage to the IM Upon receiving a stimulus, the IM proteins PspB and PspC interact with PspA, which releases PspF to activate the Psp system psp genes Brissette et al., 1990;Carlson and Silhavy, 1993;Jovanovic et al., 1996;Kobayashi et al., 1998;Jones et al., 2003 Rcs Girgis et al., 2007;Callewaert et al., 2009;Farris et al., 2010;Tao et al., 2012;Konovalova et al., 2016;Meng et al., 2020a function by inhibiting the Rcs signaling, thus ensuring that the signal through this phosphorylation is minimal in the absence of environmental stimuli (Dominguez-Bernal et al., 2004;Hussein et al., 2018;Wall et al., 2020). RcsA is an auxiliary protein that assists RcsB binding to the sites marked as RcsAB boxes (Pristovsek et al., 2003). ...
... The igaA gene is also found in other species of Enterobacterales that encode the Rcs system (Clarke, 2010). As mentioned above, the IM protein IgaA is an essential negative regulator of Rcs signaling (Dominguez-Bernal et al., 2004;Hussein et al., 2018;Wall et al., 2020). Ample evidence suggests that RcsF does not directly transmit the stress signal from the envelope to the downstream components of the Rcs system, RcsC, RcsD, and RcsB, but through the interaction with IgaA to counteract its negative regulatory effect on Rcs signaling (Cho et al., 2014;Wall et al., 2018). ...
... Ample evidence suggests that RcsF does not directly transmit the stress signal from the envelope to the downstream components of the Rcs system, RcsC, RcsD, and RcsB, but through the interaction with IgaA to counteract its negative regulatory effect on Rcs signaling (Cho et al., 2014;Wall et al., 2018). When RcsF interacts with IgaA, the Rcs system is activated (Hussein et al., 2018). ...
The bacterial cell envelope is a protective barrier at the frontline of bacterial interaction with the environment, and its integrity is regulated by various stress response systems. The Rcs (regulator of capsule synthesis) system, a non-orthodox two-component regulatory system (TCS) found in many members of the Enterobacteriaceae family, is one of the envelope stress response pathways. The Rcs system can sense envelope damage or defects and regulate the transcriptome to counteract stress, which is particularly important for the survival and virulence of pathogenic bacteria. In this review, we summarize the roles of the Rcs system in envelope stress responses (ESRs) and virulence regulation. We discuss the environmental and intrinsic sources of envelope stress that cause activation of the Rcs system with an emphasis on the role of RcsF in detection of envelope stress and signal transduction. Finally, the different regulation mechanisms governing the Rcs system’s control of virulence in several common pathogens are introduced. This review highlights the important role of the Rcs system in the environmental adaptation of bacteria and provides a theoretical basis for the development of new strategies for control, prevention, and treatment of bacterial infections.
