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Proc Natl Acad Sci U S A. May 3, 2011; 108(18): 7403–7407.
Published online Apr 18, 2011. doi:  10.1073/pnas.1019587108
PMCID: PMC3088637

Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA


Eukaryotic PIN (PilT N-terminal) domain proteins are ribonucleases involved in quality control, metabolism and maturation of mRNA and rRNA. The majority of prokaryotic PIN-domain proteins are encoded by the abundant vapBC toxin—antitoxin loci and inhibit translation by an unknown mechanism. Here we show that enteric VapCs are site-specific endonucleases that cleave tRNAfMet in the anticodon stem-loop between nucleotides +38 and +39 in vivo and in vitro. Consistently, VapC inhibited translation in vivo and in vitro. Translation-reactions could be reactivated by the addition of VapB and extra charged tRNAfMet. Similarly, ectopic production of tRNAfMet counteracted VapC in vivo. Thus, tRNAfMet is the only cellular target of VapC. Depletion of tRNAfMet by vapC induction was bacteriostatic and stimulated ectopic translation initiation at elongator codons. Moreover, addition of chloramphenicol to cells carrying vapBC induced VapC activity. Thus, by cleavage of tRNAfMet, VapC simultaneously may regulate global cellular translation and reprogram translation initiation.

Keywords: toxin-antitoxin, tRNase, riboendonuclease, tRNA, RNase

Prokaryotic toxin—antitoxin (TA) loci code for two components, a toxin that inhibits cell growth and an antitoxin that counteracts the toxin. In Type I TA loci, the antitoxins are small antisense RNAs that repress translation of the toxin genes (1, 2) while in Type II loci, the antitoxins are proteins that combine with and neutralize the toxins (3). Type III TA loci encode small RNAs that combine with and neutralize the toxins (4). Based on toxin sequence similarities, Type II loci have been divided into gene families (3, 5). Many of these gene families are present in both bacteria and archaea, predicting that the cellular targets of the toxins are of a general nature. Consistently, the RelE family of toxins, which is present in both prokaryotic domains, cleave mRNAs at codons positioned at the ribosomal A-site (6, 7). RelE toxins from archaea cleave mRNAs at A-site codons in Escherichia coli (8) and RelE from E. coli cleave A-site codons of mammalian and mitochondrial ribosomes (9, 10). The most abundant Type II TA loci are vapBC that encode PIN-domain toxins. Interestingly vapBC are highly abundant in some organisms. For example, the major human pathogen Mycobacterium tuberculosis and the hyperthermophilic chrenarchaeote Sulfolobus solfataricus have at least 45 and 30 vapBC loci, respectively (11, 12). PIN-domains (PilT N-terminal) consist of approximately 140 amino acids characterized by a quartet of conserved, negatively charged amino acid residues configured in an RNase H-like fold (Fig. S1) (13). In eukaryotes, PIN-domain proteins function in several types of RNA metabolism, such as nonsense-mediated mRNA decay (14, 15), rRNA maturation (16), and mRNA turnover (1719). Ectopic production of VapC from both Gram positive and negative bacteria efficiently inhibits cell growth by inhibiting the global rate of translation (11, 20, 21). As with other Type II TA loci, VapB antitoxins neutralize cognate VapCs by direct protein—protein interaction (21). Even though several studies showed that VapC has nonspecific ribo- or deoxyribonuclease activity in vitro, the specific target of VapC within the translation apparatus has remained elusive (11, 13, 21, 22). Here we show that VapC (MvpT) of Shigella flexneri 2a virulence plasmid pMYSH6000 (23) and VapCLT2 of Salmonella enterica serovar Typhimurium LT2, encoded by bona fide vapBC loci, are site-specific tRNases that cleave initiator tRNA between the anticodon stem and loop.


VapC Inhibits Translation In Vitro.

We showed previously that overproduction of VapC inhibits global cellular translation (21). To identify VapC’s target within the translational machinery, we purified VapC and VapCLT2. Addition of purified, native VapC to an in vitro translation reaction abolished translation (Fig. 1A, lanes 1 and 2). Preincubation with VapB antitoxin neutralized VapC activity, showing that VapCs inhibition of translation was specific (lane 3). Thus, the preparation of VapC was active in vitro and its activity could be counteracted by VapB. For reasons unknown, VapCLT2 was not active in our in vitro assays and was therefore analyzed in vivo only.

Fig. 1.
VapC inhibits translation in vitro by cleavage of tRNAfMet. (A) Native VapC inhibits translation in vitro and can be neutralized by VapB. Each reaction contained the following: 6 μL Premix, 4.5 μL S30 Extract, 1.5 μL ...

VapC Inhibits Translation by Degradation of Initiator tRNAfMet.

Ectopic production of VapC in vivo did not affect the degradation-patterns of lpp, dksA, or ompA mRNAs, ribosomal RNAs, or tmRNA (21). Consistently, VapC exhibited only weak RNase activity towards MS2 RNA in vitro (Fig. S2). Moreover, VapC did not associate specifically with 70S, 50S, or 30S ribosomal subunits (Fig. S3). Therefore, we considered that VapC might target tRNAs. VapC completely degraded purified E. coli tRNAfMet in a 15′ reaction (Fig. 1C). In contrast, tRNAVal and tRNAPhe were not degraded. Cleavage of tRNAfMet was counteracted by the prior addition of VapB to VapC, again showing specificity. EDTA also inhibited the reaction, revealing that the reaction required divalent cations (Fig. 1C). The in vitro translation reaction could only be reactivated by the addition of both VapB and fMet-tRNAfMet (Fig. 1B). The ability of fresh fMet-tRNAfMet to reactivate the reaction after quenching of VapC activity (compare lanes 3 and 4), shows that VapC does not have other targets within the translational machinery. That tRNAfMet is the sole cellular target of VapC was further substantiated by the observation that ectopic overexpression of tRNAfMet counteracted the toxic effect of a vapC pulse (Fig. S4).

VapC Cleaves Initiator tRNA Between the Anticodon Stem and Loop.

VapC degraded full-length tRNAfMet into smaller fragment(s) (Fig. 1C), indicating endonucleolytic cleavage. The cleavage was mapped to occur between +38 and +39, at the anticodon stem-loop boundary (Fig. S5). Thus, VapC is a site-specific tRNAfMet endo-nuclease in vitro. The 3′-terminus of the 5′-product of tRNAfMet could not be ligated to [5′-32P]Cytidine 3’,5’-bisphosphate (pCp) with T4 RNA ligase, consistent with a 2′,3′-cyclic phosphate. The 5′-terminus of the 3′-product could be phosphorylated without prior dephosphorylation, indicating a 5′-hydroxyl group. These observations suggest that VapC generates products similar to those of tRNA splicing endonucleases and self-cleaving ribozymes (24). Classical RNases, such as RNase T1 and A also generate these termini, but proceed to hydrolyse the cyclic phosphodiester intermediate.

The tRNase activity of VapC was investigated in E. coli. VapCLT2 from S. enterica was included in this analysis. Northern blotting showed that induction of vapC or vapCLT2 led to a rapid decrease in full-length tRNAfMet, with a concomitant appearance of smaller cleavage products (Fig. 2A top). Neither chloramphenicol nor induction of relE had this effect. Importantly, induction of vapC or vapCLT2 did not lead to cleavage of tRNAMet or seven other elongator tRNAs (An external file that holds a picture, illustration, etc.
Object name is pnas.1019587108eq1.jpg, tRNAHis, tRNAPhe, An external file that holds a picture, illustration, etc.
Object name is pnas.1019587108eq2.jpg, tRNATyr, tRNAVal, or tRNALeu) (Fig. 2A, Fig. S6). Thus, VapC cleavage of tRNAfMet was highly specific. It should be noted that tRNAfMet isoforms of E. coli, S. flexneri, and S. enterica are identical, validating the use of E. coli as the host organism in these experiments. To confirm this inference, we showed that tRNAfMet of S. enterica was also cleaved after vapCLT2 induction (Fig. S7). The complete cleavage seen both in vitro and in vivo indicates that VapC can cleave both charged and uncharged tRNAfMet (Figs. 1C and and22A).

Fig. 2.
VapC cleaves tRNAfMet in vivo. (A) Northern blotting analysis of tRNAfMet (upper) and tRNAMet (lower). MG1655Δlon containing pKW3352HC (pBAD33 :: vapCLT2-H6), pKW3382HC (pBAD33 ::vapC-H6), or pKP3035 (pBAD33:: ...

The in vivo VapC cleavage site was mapped by isolating tRNA fragments using a biotinylated tRNAfMet-specific probe. Cells expressing VapC or VapCLT2 produced tRNAfMet-derived RNAs that had sizes identical to those obtained in vitro (Fig. 2B). The slightly smaller RNA fragments also observed in vivo most likely reflect nibbling of the RNA ends after the initial cleavage. Again, neither chloramphenicol nor induction of relE produced detectable cleavage products in vivo (Fig. 2B). A sequence alignment of tRNAfMet and tRNAMet (Fig. 2C) showed that cleavage occurred between the anticodon loop and the tRNAfMet specific GC nucleotide basepair stem that acts as a discriminator for tRNAfMet loading into the ribosomal P-site (25). The GC stem is conserved in initiator tRNAs in all three domains of life.

Change of a Predicted Catalytic, Highly Conserved aa Residue Abolishes VapC Activity.

The catalytic centers of PIN-domain proteins consist of quartets of conserved, acidic aa residues (13). The sequence alignment in Fig. S1 predicted that the conserved aspartate at +7 of VapC is required for catalytic activity. To test this possibility, we changed the aspartate to alanine. As described in the following, VapCD7A indeed was inactive in vivo.

Depletion of tRNAfMet by VapC Is Reversible and Bacteriostatic.

It has been debated whether toxins encoded by TA loci are bacteriocidal or bacteriostatic. We followed the cellular content of tRNAfMet in a physiological growth experiment. After induction of vapC or vapCLT2, cell-growth ceased rapidly (Fig. 3A).

Fig. 3.
Correlation between vapC induction, cell growth, and tRNAfMet levels. (A) Bacterial growth after VapC expression and subsequent VapB expression. Strains MG1655Δlon / pKW3352HC (pBAD33 ::vapCLT2-H6) / pKW51 (R::  ...

In contrast, induction of vapCLT2D7A, that encodes a predicted catalytically inactive VapC, did not inhibit cell growth. Thirty minutes later, vapC expression was terminated and cognate vapB genes were induced. As seen, cell growth resumed ≈30 min after vapBLT2 induction and ≈90 min after vapB induction. The slower recovery after vapB induction was correlated with a more complete depletion and slower return of the cellular content of the tRNAfMet (Fig. 3 B and C). These results show that VapC can control the growth rate by depletion of tRNAfMet. The rapid resumption of cell growth and tRNAfMet recovery after induction of vapB is consistent with our previous conclusion that ectopic expression of VapC is bacteriostatic rather than bacteriocidal (21).

We showed previously that abrupt reductions in growth rate, such as the addition of chloramphenicol to rapidly growing cells, strongly activated transcription of the vapBC operon (21). This observation, however, did not tell if VapC was activated or not. The knowledge of the VapC target, however, has provided a very sensitive assay of VapC activity. As seen from Fig. 3D, addition of chloramphenicol to cells carrying vapBC on a low-copy-number plasmid induced detectable cleavage of tRNAfMet. No such cleavage was seen when the plasmid carried vapBCD7A. Thus, reduction of the growth rate can induce VapC activity, consistent with decay of VapB under this condition.

VapC Activates Initiation of Translation at Elongator Codons.

RelE is a ribosome-dependent RNase that cleaves mRNA at A-site codons, between the second and third base (6, 7). Consequently, RelE and its homologues can be used to map the position of ribosomes on a given mRNA with high resolution using primer extension analysis (10). Inhibition of translation by vapC or vapCLT2 induction leads to activation of YoeB, an E. coli RelE homologue that also cleaves mRNA between the second and third bases of A-site codons (21, 26). We showed previously that vapC induction activated YoeB such that YoeB cleaved dksA mRNA within its stop codon (26). This cleavage required translation of dksA mRNA. Here, we used vapC-induced YoeB-dependent mRNA cleavage as a sensitive measure of mRNA translation. We constructed three variants of dksA mRNA in which the Shine and Dalgarno (SD) sequence, the start-codon, or both were changed (Fig. 4A). Consistent with previous results, vapC induction resulted in ribosome-dependent YoeB cleavage within the stop codon of wild-type dksA mRNA (denoted SDwt AUG mRNA in Fig. 4A) (Fig. 4B, left, lanes 1, 2, and 5). This cleavage disappeared if the yefM yoeB TA locus was deleted from the chromosome (lanes 4 and 7) showing that the cleavage depended on activation of YoeB. Consistently, induction of yoeB encoded by a plasmid led to efficient cleavage of the wild-type dksA mRNA (lane 8). Mutational change of the SD-sequence abolished stop codon cleavage in all three cases, showing that YoeB cleavage required that the mRNA was translated (lanes 3, 6, and 9). Next, we performed a similar series of experiments on mRNAs in which the AUG start-codon had been changed to an elongator codon, AAG (Fig. 4B, right). Induction of yoeB did not lead to cleavage of the SDwt AAG mRNA, showing that the reading-frame starting with AAG was normally not translated (lanes 15, 16). In contrast, the SDwt AAG mRNA was cleaved after vapC induction (lanes 11 and 13). VapC-induced cleavage of the SDwt AAG mRNA was abolished by mutational change of the SD sequence (lanes 12 and 14). This result shows that VapC and VapCLT2 induced translation at the AAG codon of dksA mRNA if the codon was positioned correctly relative to an SD sequence. Thus, induction of vapC activated initiation of translation at elongator codons.

Fig. 4.
Ectopic production of VapC induces initiation of translation by elongator tRNAs. (A) Drawing showing the four mRNAs analyzed in (B). The top wavy lines symbolize wild-type dksA mRNA with SD, AUG start-codon, and UAA stop codon. SDmut indicates that the ...

To investigate this conjecture in a simpler and more general context, we used a dual luciferase assay to measure the fidelity of translation initiation. Firefly luciferase gene (lucF) had its AUG start-codon changed to either AAA or AAG lysine codons; renilla luciferase (lucR) was included to normalize LucF activity (Fig. 4C). The LucF/LucR ratios were very low for the AAA and AAG constructs before induction of vapCLT2, consistent with the lacking initiation of translation at the AAA and AAG elongator codons. Strikingly, induction of vapCLT2 resulted in ≈20-fold (AAA) and ≈4-fold (AAG) increases in the LucF/LucR ratios. No increase was observed when translation was inhibited with chloramphenicol or yoeB induction. These results confirmed that vapC induction activated ectopic translation initiation at elongator codons.


We show here that enteric VapCs are RNases that cleave initiator tRNA between the anticodon stem and loop. Depletion of tRNAfMet inhibited translation and, unexpectedly, activated initiation of translation at elongator codons positioned correctly relative to a ribosome binding site. Even though other site-specific tRNases are known, namely colicin D, colicin E, and PrrC, VapC is so far the only tRNase known that cleaves initiator tRNA. Colicin D cleaves four isoaccepting arginine tRNAs between +38 and +39 (27), while colicin E5 cleaves in the anticodon loop of four different elongator tRNAs, between +34 and +35 (28). Colicins are considered to be bacteriocidal, and, in contrast to VapC, are transported out of the producer cells to kill nonproducing competitor cells. Colicin-producing cells also produce immunity proteins that are analogous in function to antitoxins. PrrC, which cleaves lysine tRNA in the anticodon loop between +34 and +35, is activated by bacteriophage T4 infection (29).

VapC inhibited initiation of translation and simultaneously activated translation of reading frames that were normally silent. Whether this latter effect has physiological consequences (i.e., when endogenous VapC is activated in the wild-type context) remains to be determined. However, Varshney and colleagues observed that a reduction of the cellular level of tRNAfMet by mutations in the metZWV promoter relaxed the stringency of initiator tRNA selection at the ribosomal P-site (30). This result supports that the reduced level of tRNAfMet seen after vapC induction allows loading of elongator tRNAs in the P-site and thereby stimulates ectopic initiation of translation. The requirement for an SD sequence for ectopic initiation is in agreement with this interpretation.

Like other components of the translational apparatus, production of tRNAfMet is curtailed by the stringent response (31). Moreover, the charging level of tRNAfMet decreases in response to leucine starvation (32). Thus, bacterial cells regulate the level of tRNAfMet in response to environmental changes. The proposed regulation makes physiological sense, because a reduced rate of translation reduces both nutrient consumption and the translational error rate (33) that, in turn, may increase cellular fitness. We showed here that VapC can be activated by abrupt reduction of the growth rate (Fig. 3D). Thus vapBC may reduce the translational error rate during conditions of slow growth simply by reducing the drain on charged tRNA. In addition, it cannot be excluded that vapBC induces major changes in the proteome of slowly growing or starved cells, although this remains to be seen.

We propose that enteric VapCs represent a unique class of tRNases that are beneficial during environmental stresses. We do not exclude that vapBC TA loci play additional roles in enterics or in other organisms. However, a function as stress response elements is supported by studies showing that stressful conditions activated vapBC transcription in M. tuberculosis and S. solfataricus (11, 34). In one case, a vapBC mutant strain became temperature sensitive (34). A further example is fitAB of Neisseria gonorrhoaea, which reduces intracellular trafficing during pathogenesis, thus allowing the bacteria to better evade the immune system (35, 36). The work presented here has opened the path to identify the cellular targets of VapC PIN-domain proteins from other organisms, including M. tuberculosis.

Materials and Methods

Bacterial strains were grown in LB medium at 37 °C. When appropriate, the growth medium was supplemented with 30 μg/mL or 100 μg/mL of ampicillin for low and high-copy-number plasmids, respectively or 50 μg/mL of chloramphenicol. Transcription from LacI-regulated promoters was induced by the addition of 2 mM Isopropyl-β-D-1-thiogalactopyranoside (IPTG). Transcription from AraC-regulated promoters was induced by the addition of 0.2% arabinose. Strains and plasmids used and constructed are listed in Table S1 and oligonucleotides in Table S2. For a full description of Materials and Methods, see SI Text

Supplementary Material

Supporting Information:


We thank Ditlev Brodersen & Michael Sørensen for critical reading of the manuscript, Daniel Castro-Roa and Nikolay Zenkin for the gift of charged formyl-methionine tRNA. This work was supported by the Wellcome Trust.


The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1019587108/-/DCSupplemental.


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