## 3 Interactions of Antitoxins and Toxins with Cellular Components  
### Interactions Involving Toxins  
#### 3.1.1 Interfering with Translation  
Blocking translation appears to be the \"favorite\" inhibitory mechanism of type II toxins [74, 75, 76, 77, 78, 79]. The most common mechanism relies on mRNAs cleavage in a translation-dependent or -independent manner.  
Interactions with the ribosome: Most of the toxins belonging to the type II RelE toxin family cleave mRNAs in a translation-dependent manner by entering the ribosomal A site. These toxins usually cleave mRNAs between the second and the third nucleotide of codons or between codons [31, 80, 81]. Some RelE-like toxins appear to be devoid of specificity [31, 74, 80], while others, like _E. coli_YoeB\({}_{\text{K-12}}\), YafQ\({}_{\text{K-12}}\) and HigB from _Proteus vulgaris_, are highly specific [81, 82, 83, 84]. YoeB\({}_{\text{K-12}}\) cleaves predominantly between the start and the second codon, while YafQ\({}_{\text{K-12}}\) and HigB cleave at the AAA lysine codons [81, 82, 84]. The _E. coli_RatA, which represents another family of toxins, inhibits translation at the initiation step by specific association with the 50S sub-unit and, thereby, inhibiting 70S ribosome formation [85].  
Direct interactions with RNA targets: Interestingly, some toxins from the RelE family cleave mRNAs in a translation-independent manner like toxins from the MazE family (see below). The _E. coli_MqsR toxin is an endoribonuclease that cleaves GC[U/A] motifs [74, 86]. RelE-like toxins from _Brucella abortus_ and _Helicobacter pylori_ also act in a translation-independent manner _in vitro_[87, 88]. Type II toxins from the MazF family are endoribonucleases that cleave mRNAs specifically at either three-, four-, five- or seven-base recognition sequences [54, 75, 77, 89, 90]. Some MazF-like toxins have specialized to target specific transcripts. MazF\({}_{\text{Sa}}\) and the plasmidic PemKs\({}_{\text{Sa}}\) toxins from _Staphylococcus aureus_ recognize UACAU pentad and UAUU tetrad sequences, respectively [54, 75]. Cleavage of these motifs affects virulence in opposite ways, since the UACAU pentad is abundant in transcripts encoding virulence factors (e.g., SraP adhesive factor), while the UAUU tetrad is underrepresented in these transcripts [54]. Thus, MazF\({}_{\text{Sa}}\) down-regulates virulence gene expression [75]. The MazF\({}_{\text{-mt3}}\) and MazF\({}_{\text{-mt7}}\) of _M. tuberculosis_ cleave pentad sequences. As for PemKs\({}_{\text{Sa}}\), these motifs are underrepresented in specific genes involved in virulence [77]. Thus, these toxins appear to be involved in virulence gene expression control. Likewise, a plasmid-encoded member of the MazF family, the Kid toxin of plasmid R1, cleaves the intercistronic region of the _copB-repA_ mRNA, thereby positively regulating the R1 copy number [91].  
Recently, the three-dimensional structure of the RnIA type II toxin was solved [92]. RnIA represents a novel type II toxin family, as it does not share the fold of known toxin families. LsoA, a second member of this new family, shares 45% similarity at the amino acid sequence level with RnIA [71]. Both toxins show non-specific endoribonuclease activity [70, 71]. Finally, members of the VapC toxin family in _Shigella flexneri_ and _Salmonella enterica_ show endoribonuclease activity against initiator tRNAs [93].  
Direct interactions with factors involved in translation: Some enzymes involved in translation constitute targets for type II toxins. The P1 phage Doc toxin is a kinase and phosphorylates the EF-Tu elongation factor on a conserved threonine residue. Phosphorylated EF-Tu is unable to bind aminoacylated tRNAs, and this leads to translation inhibition [94]. The _E. coli_ HipA toxin is also a kinase [95, 96]. It phosphorylates the glutamyl-tRNA synthetase on serine 239, thereby inactivating it. This, in turn, leads to accumulation of uncharged tRNA\({}^{\text{Glu}}\) and translation inhibition [96]. Note that it was previously thought that HipA was targeting EF-Tu [95].