Antitoxin MqsA helps mediate the bacterial general stress response

Wang, Pengxia; Kim, Young-Hoon; Hong, Seok Hoon; Ma, Qun; Brown, Breann L.; Pu, Mingming; Tarone, Aaron M.; Benedik, Michael J.; Peti, Wolfgang; Page, Rebecca; Wood, Thomas K.

doi:10.1038/nchembio.560

Cited by 208 publications

(320 citation statements)

References 51 publications

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“…S7, suggest a common function of TA loci in persistence. 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).…”

Section: Discussionmentioning

confidence: 83%

“…The TA operons of E. coli that encode mRNases are induced by amino acid starvation via a Lon (Long Form Filament)-dependent mechanism (21,27,28). Direct evidence of Lon degradation of antitoxins has been obtained for RelB, MqsA, and YefM (27,29) (Fig. S2), whereas indirect evidence has been obtained in the cases of MazE, MazE-2 (ChpBI), HicB, YafN, and YgjM (HigA) (19,28).…”

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confidence: 93%

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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: 83%

mentioning

confidence: 93%

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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“…Second, more than 60 TA toxins are conserved between five members of the M. tuberculosis complex but not in 13 other closely related mycobacteria (9), raising the possibility that the large number of TA systems in M. tuberculosis is specifically important for TB pathogenesis. Third, TA systems have intriguing connections to stress responses and persistence, both in E. coli (1,2,11,12) and in M. tuberculosis (9,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Various TA loci in M. tuberculosis are induced during heat shock (23), hypoxia (9,21), DNA damage (20), nutrient starvation (13), macrophage infection (9,14,18), and antibiotic treatment (19,22), whereas other TA loci are down-regulated during macrophage infection (16) or salicylate treatment (15).…”

mentioning

confidence: 99%

Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site

Schifano

Edifor

Sharp

et al. 2013

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

116

123

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The Mycobacterium tuberculosis genome contains an unusually high number of toxin-antitoxin modules, some of which have been suggested to play a role in the establishment and maintenance of latent tuberculosis. Nine of these toxin-antitoxin loci belong to the mazEF family, encoding the intracellular toxin MazF and its antitoxin inhibitor MazE. Nearly every MazF ortholog recognizes a unique three-or five-base RNA sequence and cleaves mRNA. As a result, these toxins selectively target a subset of the transcriptome for degradation and are known as "mRNA interferases." Here we demonstrate that a MazF family member from M. tuberculosis, MazF-mt6, has an additional role-inhibiting translation through targeted cleavage of 23S rRNA in the evolutionarily conserved helix/loop 70. We first determined that MazF-mt6 cleaves mRNA at 5′ UU↓CCU 3′ sequences. We then discovered that MazF-mt6 also cleaves M. tuberculosis 23S rRNA at a single UUCCU in the ribosomal A site that contacts tRNA and ribosome recycling factor. To gain further mechanistic insight, we demonstrated that MazFmt6-mediated cleavage of rRNA can inhibit protein synthesis in the absence of mRNA cleavage. Finally, consistent with the position of 23S rRNA cleavage, MazF-mt6 destabilized 50S-30S ribosomal subunit association. Collectively, these results show that MazF toxins do not universally act as mRNA interferases, because MazF-mt6 inhibits protein synthesis by cleaving 23S rRNA in the ribosome active center.T oxin-antitoxin (TA) systems have the potential to control Mycobacterium tuberculosis growth rate and persistence. One of the best characterized TA modules is mazEF in Escherichia coli (1-7), an autoregulated operon that encodes the intracellular toxin MazF and its antitoxin inhibitor MazE. Under unstressed conditions, the MazE protein forms a stable complex with MazF to neutralize its toxicity (1). During times of stress, however, proteases degrade MazE and allow the relatively stable MazF toxin to disrupt protein synthesis (1, 2), which can induce a state of reversible dormancy (3). Expression of MazF triggers this quasi-dormant state, during which cells stop dividing but are able to transcribe mRNA and synthesize proteins (4). The striking similarities between this state of quasi-dormancy and the slowgrowing or nonreplicating state of M. tuberculosis during latent tuberculosis (TB) have led to the suggestion that TA modules are involved with persistence and dormancy in M. tuberculosis (8).The genome of M. tuberculosis has >80 putative TA pairs (9), a remarkably large number relative to most other prokaryotes. Although TA modules are ubiquitous in bacteria and archaea, few prokaryotes have more than 15 loci (10). Although the physiological role of the large repertoire of TA loci in M. tuberculosis is largely unknown, some clues have emerged. First, there is an inverse correlation between the number of chromosomal TA loci and growth rate (10). Second, more than 60 TA toxins are conserved between five members of the M. tuberculosis complex but not in 13 oth...

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“…It has been shown that, in many cases, the unfolded nature of the antitoxin protein or its unstructured C-terminal domain is the cause of its vulnerability to degradation by intracellular proteases. In most cases, the Lon protease, which represents a major class of ATP-dependent proteases, is involved in antitoxin degradation (2)(3)(4)(5)(6)(7)(8)(9)(10). There are also known TA systems that use the two-component protease ClpP, which cooperates with the ATPase-active chaperones ClpA or ClpX (11,12).…”

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confidence: 99%