Crystal structure of archaeal toxin-antitoxin RelE–RelB complex with implications for toxin activity and antitoxin effects

Takagi, Hisanori; Kakuta, Yoshimitsu; Okada, Takahiro; Yao, Min; Tanaka, Isao; Kimura, Makoto

doi:10.1038/nsmb911

Cited by 150 publications

(219 citation statements)

References 39 publications

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“…On the other hand, these observations, of course, do not exclude that particular TA loci have been recruited to perform other functions, as recently proposed for the mqsRA locus of E. coli (47). The entirely different tertiary folds of the translational inhibitors encoded by type II TA loci, such as RelE, MazF, and HicA, indicate that they have independent evolutionary origins (7,15,(48)(49)(50)(51). Therefore, the common genetic organization, transcriptional regulation, and cellular targets (i.e., translation) of type II TA loci suggest that these gene families emerged by convergent evolution.…”

Section: Discussionmentioning

confidence: 84%

RETRACTED: Bacterial persistence by RNA endonucleases

Maisonneuve

Shakespeare

Jørgensen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

459

557

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Bacteria form persisters, individual cells that are highly tolerant to different types of antibiotics. Persister cells are genetically identical to nontolerant kin but have entered a dormant state in which they are recalcitrant to the killing activity of the antibiotics. The molecular mechanisms underlying bacterial persistence are unknown. Here, we show that the ubiquitous Lon (Long Form Filament) protease and mRNA endonucleases (mRNases) encoded by toxin-antitoxin (TA) loci are required for persistence in Escherichia coli . Successive deletion of the 10 mRNase-encoding TA loci of E . coli progressively reduced the level of persisters, showing that persistence is a phenotype common to TA loci. In all cases tested, the antitoxins, which control the activities of the mRNases, are Lon substrates. Consistently, cells lacking lon generated a highly reduced level of persisters. Moreover, Lon overproduction dramatically increased the levels of persisters in wild-type cells but not in cells lacking the 10 mRNases. These results support a simple model according to which mRNases encoded by TA loci are activated in a small fraction of growing cells by Lon-mediated degradation of the antitoxins. Activation of the mRNases, in turn, inhibits global cellular translation, and thereby induces dormancy and persistence. Many pathogenic bacteria known to enter dormant states have a plethora of TA genes. Therefore, in the future, the discoveries described here may lead to a mechanistic understanding of the persistence phenomenon in pathogenic bacteria.

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Section: Discussionmentioning

confidence: 84%

RETRACTED: Bacterial persistence by RNA endonucleases

Maisonneuve

Shakespeare

Jørgensen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

459

557

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“…In E. coli, relBE appears to be part of a complex bacterial response to nutrient starvation (60). Importantly, a crystal structure of the RelBE protein-protein complex was recently solved (61).…”

Section: Discussionmentioning

confidence: 99%

Toxin–antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci

Moritz¹,

Hergenrother

2007

Proc. Natl. Acad. Sci. U.S.A.

124

127

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Vancomycin-resistant enterococci (VRE) are common hospital pathogens that are resistant to most major classes of antibiotics. The incidence of VRE is increasing rapidly, to the point where over one-quarter of enterococcal infections in intensive care units are now resistant to vancomycin. The exact mechanism by which VRE maintains its plasmid-encoded resistance genes is ill-defined, and novel targets for the treatment of VRE are lacking. In an effort to identify novel protein targets for the treatment of VRE infections, we probed the plasmids obtained from 75 VRE isolates for the presence of toxin-antitoxin (TA) gene systems. Remarkably, genes for one particular TA pair, the mazEF system (originally identified on the Escherichia coli chromosome), were present on plasmids from 75/75 (100%) of the isolates. Furthermore, mazEF was on the same plasmid as vanA in the vast majority of cases (>90%). Plasmid stability tests and RT-PCR raise the possibility that this plasmidencoded mazEF is indeed functional in enterococci. Given this ubiquity of mazEF in VRE and the deleterious activity of the MazF toxin, disruption of mazEF with pharmacological agents is an attractive strategy for tailored antimicrobial therapy.antibiotics ͉ mazEF ͉ axe-txe ͉ relbE ͉ VRE E nterococci are the leading cause of surgical-site infections and the third leading cause of urinary tract and bloodstream infections (1, 2) and are implicated in bacterial endocarditis, intraabdominal infections, bacteremia, and meningitis (3). The intrinsic resistance of enterococci to cephalosporin and aminoglycoside antibiotics complicates treatment strategies. Historically, vancomycin has been effective in the management of enterococcal infections; however, after nearly 30 years of use, vancomycin-resistant enterococci (VRE) emerged in the mid-1980s. In a short time span, intensive care units in the U.S. have seen a dramatic increase in the percentage of enterococcal infections that are resistant to vancomycin, from 0. 4% in 1989 to 25% in 1999 (3). In fact, in a recent study, 60% of Enterococcus faecium clinical isolates were resistant to vancomycin (4).The genes encoding the elaborate protein systems that mediate vancomycin resistance generally reside on mobile genetic elements within the enterococci. In some cases, plasmids with the various vancomycin resistance gene clusters have been recovered from enterococci (5-8), although the prevalence of plasmid-encoded resistance in VRE has not been defined. Large plasmids often have intricate mechanisms by which they maintain themselves in the bacterial population. Some plasmids contain genes encoding postsegregational killing ''plasmid addiction'' systems (9, 10), in which the plasmid encodes a potent toxin and a labile antitoxin. Provided the plasmid is present, the antitoxin binds to and sequesters the toxin. However, if a plasmid-free daughter cell arises, the unstable antitoxin is degraded, and the toxic protein kills the bacterial cell from within.If toxin-antitoxin (TA) systems are prevalent and functional on ...

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“…Then we subjected the ribosome profile fractions to Western blotting analysis using antibodies to His-tag, because aRelE was prepared with His-tag at its C-terminus, as described previously. 15) The results indicated that aRelE bound the 70S ribosome only in the presence of the mRNAs (Fig. 3A, c-f), though no aRelE was detected in the 70S ribosome fractions in the absence of mRNA (Fig.…”

mentioning

confidence: 83%

“…15) A mutation of Arg85 in aRelE significantly reduced protein synthesis inhibitory activity. 15) In this study, to examine the involvement of Arg85 in inhibitory activity in more detail, Arg85 was replaced by Glu, Trp, His, and Lys, and the resulting mutants were prepared in the same manner as the wild-type and were characterized with respect to inhibitory activity using the E. coli T7 S30 Extract System, as described previously. 15) Figure 2 shows the inhibitory profiles of the mutants.…”

mentioning

confidence: 98%

“…15) In this study, to examine the involvement of Arg85 in inhibitory activity in more detail, Arg85 was replaced by Glu, Trp, His, and Lys, and the resulting mutants were prepared in the same manner as the wild-type and were characterized with respect to inhibitory activity using the E. coli T7 S30 Extract System, as described previously. 15) Figure 2 shows the inhibitory profiles of the mutants. Two mutants, R85H and R85K, in which Arg85 was replaced with His and Lys respectively, possessed inhibitory activity comparable to the wild type; the two mutants significantly reduced in vitro translation, up to 20%, as judged by the incorporation of [ 35 S]-methionine.…”

mentioning

confidence: 99%

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