Chapter 11 : Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding

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Toxin-antitoxin (TA) systems are, by definition, simple genetic loci composed of two genes: a toxin and an antitoxin that counteracts either the toxin’s action or its expression. Usually, toxin synthesis leads to growth arrest or death of the bacterium that produces it by inhibiting essential cellular processes such as replication, translation, or cell division ( ). Analogies can be made with other gene pairs with a similar bicistronic operon organization, such as bacteriocins, restriction-modification systems, and type VI secretion system effector/immunity proteins ( ). For instance, they are often found within mobile genetic elements and pathogenicity islands. However, canonical TA systems generally act on the cell that produces them, and in contrast to bacteriocins, they are not involved in interbacterial competition. Thus, the presence of TA-encoded toxins in bacterial genomes strongly depends on the expression of their cognate antitoxins ( ). TA systems can be classified into six different types depending on the nature and mode of action of the antitoxin (for a review, see reference ). While the toxins are always proteins, antitoxins can be either proteins (types II, IV, V, and VI) or small RNAs (sRNAs, types I and III TA systems). Antitoxins can act by (i) sequestering the toxin (types II and III), (ii) inhibiting its expression (types I and V), or (iii) counterbalancing its activity (type IV). In this review, we will focus on type I TA systems, in which an antisense RNA plays the role of antitoxin to prevent the synthesis of its cognate toxin by directly base-pairing to the mRNA.

Citation: Masachis S, Darfeuille F. 2019. Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding, p 173-190. In Storz G, Papenfort K (ed), Regulating with RNA in Bacteria and Archaea. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.RWR-0030-2018
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Figure 1

Various modes of antitoxin-mediated regulation. The three main types of toxicity regulation by antitoxins. (A) Direct sequestration. In types II and VI TA systems, toxin inactivation involves a direct interaction between the toxin (T) and the antitoxin (A). The formation of an inactive TA heterocomplex (T-A) can, in its turn (for type II), lead to the transcriptional repression of the operon (red star). In type VI, the formation of the inactive TA complex favors toxin degradation by cellular proteases (yellow circle). In type III, the antitoxin is an RNA that directly binds to the toxin to prevent its toxic activity. (B) Antagonism. Both toxin and antitoxin compete for binding to the same target. The interaction can additionally have opposite functional (antagonistic) effects. (C) Control of expression. In types I and V, regulation occurs at the posttranscriptional level. In type I, antitoxins are antisense RNA molecules that base-pair to the toxin-encoded mRNA to alter its expression by either inhibiting translation initiation or promoting its degradation. In type V, the antitoxin is an RNase that cleaves the toxin-encoded mRNA.

Citation: Masachis S, Darfeuille F. 2019. Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding, p 173-190. In Storz G, Papenfort K (ed), Regulating with RNA in Bacteria and Archaea. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.RWR-0030-2018
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Figure 2

Illustration of the consequences of transcription/translation uncoupling for regulation of type I TA expression. (A) The lack of nuclear compartmentalization in bacteria leads to the coupling in time and space of transcription and translation processes. (B) Transcription/translation coupling of type I toxin-encoding mRNAs would be lethal. TA systems can be conserved in bacterial genomes thanks to the decoupling of such processes through the sequestration of the SD sequence (red) during transcription . This SD sequestration is conserved in primary transcripts, making them unable to interact with both ribosomes and antitoxin sRNAs . In the cases where SD sequence sequestration involves a 5′-3′ LDI, the formation of successive metastable structures ensuring SD inaccessibility to both ribosomes and antitoxin during transcription is essential to prevent premature toxin expression and mRNA degradation, respectively. Translational activation is achieved by the enzymatic processing (of the 5′ or 3′ mRNA end, depending on the TA system) of the primary transcript followed by a structural rearrangement that renders the mRNA able to interact with both ribosomes and the antitoxin . Ribosome binding to the accessible SD sequence (green) leads to toxin production, inducing either growth arrest or cell death . On the opposite, antitoxin binding efficiently inhibits toxin translation and promoter mRNA degradation, allowing cell survival .

Citation: Masachis S, Darfeuille F. 2019. Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding, p 173-190. In Storz G, Papenfort K (ed), Regulating with RNA in Bacteria and Archaea. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.RWR-0030-2018
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Figure 3

Examples of secondary structures sequestering the SD sequence of toxin-encoding mRNAs. (A) Stem-loop sequences in which the SD sequence is totally or partially sequestered by an upstream aSD sequence. These secondary structures have been experimentally validated ( ) or predicted (indicated by *) ( ). For BsrG, the stem-loop sequestering the SD is shown in absence of SR4 antitoxin (**). Indeed, when the antitoxin binds to the mRNA, the stem-loop sequestering the SD is extended by 4 additional base pairs ( ). (B) Stem-loop structures sequestering the SD sequence of the Mok leader peptide and the Hok toxin. In this case, the formation of the Mok SD-sequestering stem-loop is dependent on a 5′-3′ LDI ( ). (C) Examples of SD sequestration achieved by a stable LDI between both mRNA ends, creating a cloverleaf structure ( ). The start codon (AUG, shown in green) can additionally be partially or totally sequestered in one of the cloverleaf structures. Dotted gray lines indicate the presence of unrepresented structures/lengths. Full gray lines schematically represent structures and base pairs. SD sequences are shown in red; aSD sequences are shown in black. Positions are relative to the transcription start site of the mRNAs (+1). 5′ and 3′ indicate orientation of the mRNA. Toxin mRNA names are indicated under each structure. The small index next to each name indicates the host organisms: Ec, ; Bs, ; Ef, ; Sa, ; and Hp, .

Citation: Masachis S, Darfeuille F. 2019. Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding, p 173-190. In Storz G, Papenfort K (ed), Regulating with RNA in Bacteria and Archaea. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.RWR-0030-2018
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Figure 4

Type I operon organization in Gram-negative bacteria and mechanistic consequences of its regulation. Type I antitoxin sRNAs in Gram-negative bacteria can be encoded in two main fashions: (i) overlapping the 5′ end of the toxin mRNA, the ORF, or a leader ORF (left panel) or (ii) not overlapping (right panel). In both cases, transcription/translation coupling forces the sequestration of the SD sequence by partially or totally complementary sequences called anti-SD (aSD). This sequestration starts during transcription but is maintained upon transcription termination, leading to the generation of a translationally inert and sRNA-inaccessible primary transcript (full-length mRNA). Location of the aSD sequence will determine whether the sequestration occurs via 5′-3′ LDI (5′-overlapping TA loci) or in a stem-loop (nonoverlapping TA loci). In both cases, an enzymatic activation step is required for the generation of the truncated (active) mRNA. When the SD sequestration involves 5′-3′ interaction, this activation step often occurs via 3′ trimming by 3′-5′ exonucleases (RNaseII, PNPase). In contrast, when SD is sequestered in a stem-loop, activation occurs via 5′-end processing by endonucleases. In either case, a light or strong structural rearrangement (refolding) is needed upon processing to render the SD accessible to both ribosomes and sRNA binding. Next, in noninduced conditions, antitoxin sRNAs outcompete the ribosomes for binding to the 5′ end of the toxin mRNA and render it translationally inert. This inactivation step can occur via direct sequestration of the SD sequence or the leader ORF SD sequence (5′-overlapping TA loci), or indirectly via the sequestration of the ribosome standby site (stand-by) or the stabilization of an SD-trapped structure (nonoverlapping TA loci). In most cases, sRNA binding to the toxin mRNA leads to RNase III-mediated toxin mRNA decay and cell survival.

Citation: Masachis S, Darfeuille F. 2019. Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding, p 173-190. In Storz G, Papenfort K (ed), Regulating with RNA in Bacteria and Archaea. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.RWR-0030-2018
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Figure 5

Mechanistic regulatory consequences of the 3′-overlapping antitoxin sRNAs in Gram-positive bacteria. In all type I TAs described so far in Gram-positive bacteria, antitoxin sRNAs are encoded in 3′-overlapping fashion to the toxin mRNAs. As in Gram-negative bacteria, transcription/translation coupling forces the sequestration of the SD sequence during transcription, the nascent transcript being accessible neither for the ribosome nor the antitoxin. Upon transcription termination, the full-length mRNA becomes targeted by the antitoxin RNA that binds to the 3′ end of the toxin mRNA. The question marks represent how mRNA activation could occur in Gram-positive bacteria (little is known about the mRNA activation, processing, or refolding steps compared to Gram-negative bacteria). In some cases (TxpA and YonT), sRNA binding is not sufficient to impede toxin translation, and thus, mRNA degradation by RNase III is essential to avoid toxicity. In some cases, sRNA binding leads to a structural rearrangement that enhances the sequestration of the SD sequence. This interaction can in its turn lead to mRNA degradation by RNase III or on the contrary to the stabilization of the translationally inert complex. In all cases, antitoxin binding to the toxin mRNA hampers its expression and allows cell survival.

Citation: Masachis S, Darfeuille F. 2019. Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding, p 173-190. In Storz G, Papenfort K (ed), Regulating with RNA in Bacteria and Archaea. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.RWR-0030-2018
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Table 1

Type I TA systems identified in bacteria

Citation: Masachis S, Darfeuille F. 2019. Type I Toxin-Antitoxin Systems: Regulating Toxin Expression via Shine-Dalgarno Sequence Sequestration and Small RNA Binding, p 173-190. In Storz G, Papenfort K (ed), Regulating with RNA in Bacteria and Archaea. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.RWR-0030-2018

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