## 8 Type II TAs that Regulate Other Genes or Do Not Display Autoregulation  
The _mqsR4_ module encoded by _E. coli_ displays many features that differ from canonical type II TA systems. First, the gene for the _mqsR_ toxin precedes the _mqsA_ antitoxin gene, whereas the standard organization comprises an antitoxin gene followed by a toxin gene (Figure 1). This unusual genetic organization has been observed only rarely in other TA systems characterized to date, including the _higBA_[105] and _hicAB_ modules [106]. Second, the MqsA antitoxin is well-ordered throughout its entire length and requires zinc ions to maintain its structural stability, properties that are unique among known antitoxins (Figure 2D) [48]. Autoregulation of the _mqsRA_ module also is distinctive. The antitoxin repressor, MqsA, undergoes extensive domain rearrangements upon DNA binding and is the only antitoxin known to interact with DNA via its C-terminal domain [48, 107]. However, the MqsA N-terminal domain, which binds the MqsR toxin, also makes direct interactions with DNA. It twists and collapses over the DNA and this rotation clamps the DNA thereby enhancing binding [107]. Interestingly, the MqsR toxin does not function as a transcriptional corepressor as in many other TA systems. Instead, MqsR destabilizes the MqsA-DNA complex. This reflects that the binding sites of DNA and MqsR on MqsA partially overlap rendering simultaneous binding of both by MqsA impossible. Thus, MqsR is a transcriptional activator of _mqsR4_ expression, not a transcriptional repressor [85]. Distinct from other type II TA systems, the MqsR-MqsA complex also regulates other genomic promoter regions. Specifically, the MqsA antitoxin and the MqsR-MqsA complex regulate the promoters of genes that are important for _E. coli_ metabolism, including the _mcbR_, _spy_ and _cspD_ loci [48, 108]. The _mcbR_ gene encodes a colonic acid regulator, Spy is a periplasmic chaperone of proteins, and CspD is a stress-induced cold shock protein that is a DNA replication inhibitor. MqsA also directly binds to an MqsRA-like palindrome located within the promoter of the _rpoS_ gene and thereby represses transcription of a major regulator of stress, \(\sigma^{\mathrm{S}}\)[109]. This lowers the concentration of the internal messenger 3,5-cyclic diguanylic acid (c-di-GMP) which in turn causes increased motility and reduction of biofilm formation, as well as decreased oxidative stress resistance through catalase activity [107]. MsqA also modulates biofilm formation by acting as a transcriptional regulator of the gene that encodes CsgD, a master controller of biofilm formation [110]. The endoribonuclease toxin MqsR is also a global regulator [108, 111]. It cleaves specific mRNA mainly at 5'-GCU-3' sites [112, 113] which significantly increases the presence of mRNAs coding for CtsA, CspD, RpoS, Dps and HokD proteins that are known to be associated with stress response [108]. Thus, the MqsR-MqsA system controls cell physiology both by its own toxicity as well as through the regulation of other genes. The chromosomal _mazE-mazF_ operon of _Staphylococcus aureus_ is transcriptionally linked to the downstream, polycistronic _sigB_ operon and is transcribed both as part of the operon and as a shorter transcript. Unlike the homologous genes in _E. coli_, staphylococcal _mazE-mazF_ is not subject to autoregulation. Instead, the activity of the _mazE-mazF_ promoter is inhibited by the product of the _sigB_ gene that codes for the alternative sigma factor, \(\sigma^{\mathrm{B}}\). Moreover, the _mazE-mazF_ promoter is required for full \(\sigma^{\rm B}\) activity due both to its transcriptional coupling with the _sigB_ operon via readthrough of a weak downstream _rho_-independent terminator and to the ability to respond to multiple stresses [114]. On the other hand, the _mazE-mazF_ promoter is positively and directly regulated by SarA, a winged-helix, global transcriptional regulator of virulence gene expression in _S. aureus_[115].