A Highly Conserved Bacterial D-Serine Uptake System Links Host Metabolism and Virulence

Connolly, James P. R.; Gabrielsen, Mads; Goldstone, Robert; Grinter, Rhys; Wang, Da‐Wei; Cogdell, Richard J.; Walker, Daniel; Smith, David George Emslie; Roe, Andrew J.

doi:10.1371/journal.ppat.1005359

Cited by 56 publications

(68 citation statements)

References 76 publications

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“…Alternative names exist for cyuP (cdsA and dlsT), cyuA (cdsB), and cyuR (cutR and decR) (21)(22)(23). Nonetheless, we propose the cyu designation because the cds designation (for CDP-diglyceride synthetase) and the cut designation (for copper utilization) are already in use, and the dec designation (for detoxification of cysteine) does not suggest expression of these genes and the phenotype of mutants lacking these genes when cysteine is not toxic (described below).…”

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confidence: 99%

Anaerobic Cysteine Degradation and Potential Metabolic Coordination in Salmonella enterica and Escherichia coli

et al. 2017

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Salmonella enterica has two CyuR-activated enzymes that degrade cysteine, i.e., the aerobic CdsH and an unidentified anaerobic enzyme; Escherichia coli has only the latter. To identify the anaerobic enzyme, transcript profiling was performed for E. coli without cyuR and with overexpressed cyuR. Thirty-seven genes showed at least 5-fold changes in expression, and the cyuPA (formerly yhaOM) operon showed the greatest difference. Homology suggested that CyuP and CyuA represent a cysteine transporter and an iron-sulfur-containing cysteine desulfidase, respectively. E. coli and S. enterica ΔcyuA mutants grown with cysteine generated substantially less sulfide and had lower growth yields. Oxygen affected the CyuRdependent genes reciprocally; cyuP-lacZ expression was greater anaerobically, whereas cdsH-lacZ expression was greater aerobically. In E. coli and S. enterica, anaerobic cyuP expression required cyuR and cysteine and was induced by L-cysteine, D-cysteine, and a few sulfur-containing compounds. Loss of either CyuA or RidA, both of which contribute to cysteine degradation to pyruvate, increased cyuP-lacZ expression, which suggests that CyuA modulates intracellular cysteine concentrations. Phylogenetic analysis showed that CyuA homologs are present in obligate and facultative anaerobes, confirming an anaerobic function, and in archaeal methanogens and bacterial acetogens, suggesting an ancient origin. Our results show that CyuA is the major anaerobic cysteine-catabolizing enzyme in both E. coli and S. enterica, and it is proposed that anaerobic cysteine catabolism can contribute to coordination of sulfur assimilation and amino acid synthesis.IMPORTANCE Sulfur-containing compounds such as cysteine and sulfide are essential and reactive metabolites. Exogenous sulfur-containing compounds can alter the thiol landscape and intracellular redox reactions and are known to affect several cellular processes, including swarming motility, antibiotic sensitivity, and biofilm formation. Cysteine inhibits several enzymes of amino acid synthesis; therefore, increasing cysteine concentrations could increase the levels of the inhibited enzymes. This inhibition implies that control of intracellular cysteine levels, which is the immediate product of sulfide assimilation, can affect several pathways and coordinate metabolism. For these and other reasons, cysteine and sulfide concentrations must be controlled, and this work shows that cysteine catabolism contributes to this control.

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confidence: 99%

Anaerobic Cysteine Degradation and Potential Metabolic Coordination in Salmonella enterica and Escherichia coli

et al. 2017

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“…However, we have observed growth tolerance of EHEC irrespective of sulA upregulation, suggesting that there are downstream factors that counteract the effects of increased SulA expression. What is most intriguing is that this tolerance appears to be unique to EHEC, given that a UPEC ⌬dsdA mutant is unable to tolerate D-serine accumulation and shows arrested growth under the same conditions (41). These results suggest EHEC-specific regulation that counteracts recA induction by D-serine.…”

Section: Discussionmentioning

confidence: 97%

“…In this work, we found that D-serine accumulation could actually enhance the mutation rate of the population through RecA production and that this was dependent on D-serine accumulation in the cell. Interestingly, D-serine accumulation in a UPEC ⌬dsdA background is a much less tolerated event and exemplifies a fitness defect under these conditions (41). In the UPEC ⌬dsdA mutant, D-serine accumulation also results in a higher recA induction than that of EHEC, suggesting that this stress may account for the apparent adaptation to D-serine tolerance in EHEC.…”

Section: Discussionmentioning

confidence: 99%

“…EHEC counterintuitively uses this system to increase D-serine uptake in its presence but is capable of tolerating D-serine accumulation without actively breaking down this toxic metabolite. However, despite this apparent tolerance, expression of the SOS regulon persists, suggesting a mechanism of transcriptionally responding to this signal in order to quickly adapt to changing D-serine concentrations that may be encountered (31,41). Furthermore, SOS activation can lead to an increased mutational frequency and, in turn, increase bacterial fitness after exposure to even subinhibitory concentrations of antibiotics, for example (38,39,52).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, a D-serine deaminase (⌬dsdA) mutant uropathogenic E. coli (UPEC) strain displayed decreased fitness under the same conditions (41). We thus postulated that E. coli strains normally capable of catabolizing D-serine would be susceptible to D-serine-mediated stress in the absence of dsdA.…”

Section: Intracellular Accumulation Of D-serine Increases Reca Producmentioning

confidence: 99%

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Intracellular d -Serine Accumulation Promotes Genetic Diversity via Modulated Induction of RecA in Enterohemorrhagic Escherichia coli

Connolly

Roe

2016

J Bacteriol

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We recently discovered that exposure of enterohemorrhagic Escherichia coli (EHEC) to D-serine resulted in accumulation of this unusual amino acid, induction of the SOS regulon, and downregulation of the type III secretion system that is essential for efficient colonization of the host. Here, we have investigated the physiological relevance of this elevated SOS response, which is of particular interest given the presence of Stx toxin-carrying lysogenic prophages on the EHEC chromosome that are activated during the SOS response. We found that RecA elevation in response to D-serine, while being significant, was heterogeneous and not capable of activating stx expression or stx phage transduction to a nonlysogenic recipient. This "SOS-like response" was, however, capable of increasing the mutation frequency associated with low-level RecA activity, thus promoting genetic diversity. Furthermore, this response was entirely dependent on RecA and enhanced in the presence of a DNA-damaging agent, indicating a functional SOS response, but did not result in observable cleavage of the LexA repressor alone, indicating a controlled mechanism of induction. This work demonstrates that environmental factors not usually associated with DNA damage are capable of promoting an SOS-like response. We propose that this modulated induction of RecA allows EHEC to adapt to environmental insults such as D-serine while avoiding unwanted phage-induced lysis. IMPORTANCEThe SOS response is a global stress network that is triggered by the presence of DNA damage due to breakage or stalled replication forks. Activation of the SOS response can trigger the replication of lytic bacteriophages and promote genetic diversification through error-prone polymerases. We have demonstrated that the host-associated metabolite D-serine contributes to Escherichia coli niche specification and accumulates inside cells that cannot catabolize it. This results in a modulated activation of the SOS antirepressor RecA that is insufficient to trigger lytic bacteriophage but capable of increasing the SOS-associated mutation frequency. These findings describe how relevant signals not normally associated with DNA damage can hijack the SOS response, promoting diversity as E. coli strains adapt while avoiding unwanted phage lysis. The bacterial SOS response is a global network of DNA repair proteins that is triggered in the presence of DNA replication inhibition, DNA strand breaks, or DNA-damaging agents such as antibiotics, UV light, reactive oxygen species, and pressure (1, 2). The SOS regulon is under the control of the LexA repressor and consists of Ͼ40 genes in Escherichia coli (1, 3-5). Upon DNA damage, the LexA antirepressor RecA is activated by forming a filament structure with single-stranded DNA and promotes autocatalytic cleavage of LexA, thus relieving the repression of SOSregulated genes (6-9). A second mechanism of SOS induction has also been described that involves the two-component sensor DpiAB, which activates the SOS network in response to ␤-lactam an...

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Interbacterial Chemical Communication‐Triggered Nascent Proteomics

et al. 2022

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Metabolic labeling with clickable noncanonical amino acids has enabled nascent proteome profiling, which can be performed in a cell-type-specific manner. However, nascent proteomics in an intercellular communication-dependent manner remains challenging. Here we develop communication-activated profiling of protein expression (CAPPEX), which integrates the LuxI/ LuxR quorum sensing circuit with the cell-type-specific nascent proteomics method to enable selective clicklabeling of newly synthesized proteins in a specific bacterium upon receiving chemical signals from another reporter bacterium. CAPPEX reveals that E. coli competes with Salmonella for tryptophan as the precursor for indole, and the resulting indole suppressed the expression of virulence factors in Salmonella. This tryptophan-indole axis confers attenuation of Salmonella invasion in host cells and living mice. The CAPPEX strategy should be widely applicable for investigating various interbacterial communication processes.

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A Highly Conserved Bacterial D-Serine Uptake System Links Host Metabolism and Virulence

Cited by 56 publications

References 76 publications

Anaerobic Cysteine Degradation and Potential Metabolic Coordination in Salmonella enterica and Escherichia coli

Anaerobic Cysteine Degradation and Potential Metabolic Coordination in Salmonella enterica and Escherichia coli

Intracellular d -Serine Accumulation Promotes Genetic Diversity via Modulated Induction of RecA in Enterohemorrhagic Escherichia coli

Interbacterial Chemical Communication‐Triggered Nascent Proteomics

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