## 3 Cellular Roles of YchF/Ola1 in Stress Response  
Multiple studies have linked YchF/Ola1 to stress response pathways [20; 21; 22; 26; 39]. Intriguingly, the absence/depletion of YchF/Ola1 leads to a gain of function phenotype in some cases, i.e., the corresponding strains tolerate non-favourable conditions much better than wild type cells. This is shown for the \(\Delta ychF\) strain of _E. coli_, which is resistant against the replication inhibitor hydroxyurea and the translational inhibitor fusidic acid [42]. The reversal of these phenotypes is observed by providing just \(ychF\) in trans, demonstrating that the observed phenotypes are not caused by a reduced expression of the \(pth\) gene, which forms a bicistronic transcript together with \(ychF\)[20; 26; 42]. Other examples for a stress-related function of YchF/Ola1 is the increased resistance of Ola1-depleted cells against DNA-damaging agents [61; 62] or the increased salt sensitivity of plants, when YchF is over-produced [22; 46; 56]. Even though in some cases the absence of YchF/Ola1 is beneficial for cells encountering stress conditions, the \(\Delta ychF\) strain is rapidly outcompeted by wild type _E. coli_ cells under non-stress conditions [42], pointing to an important role of YchF in cellular metabolism. This is also supported by the cold sensitivity of the \(\Delta ychF\) strain. The cold-sensitive phenotype is rescued by a plasmid-borne copy of wild type \(ychF\) but not by the ATPase-deficient mutant [20], suggesting that ATP hydrolysis is required for growth at sub-optimal temperatures. Cold sensitivity in bacteria is frequently associated with changes in membrane composition, e.g., alterations in lipid or protein composition [63; 64]. Whether the absence of YchF has any impact on lipid or protein composition of the bacterial membrane is currently unknown, but the reduced iron uptake in \(\Delta ychF\) strains of _Vibrio vulnificus_ and _Brucella melitensis_ could support possible membrane alterations [51; 54]. A common phenotype of \(ychF\)-deletion strains of _E. coli_ and Ola1-depleted human cells is their increased resistance to reactive oxygen species (ROS), such as peroxides, and to thiol-depleting agents, such as diamide [20; 21; 26]. In _E. coli_, \(ychF\) expression is downregulated when cells are exposed to H\({}_{2}\)O\({}_{2}\)[20], indicating that lowering the YchF concentration is a physiological response against ROS accumulation. Accumulating H\({}_{2}\)O\({}_{2}\) activates the oxidative stress-responsive transcription factor OxyR [65], which recognizes a specific binding motif within the 5\({}^{\prime}\)-UTR of \(ychF\) and prevents transcription initiation [20]. The transcriptional downregulation of \(ychF\) in _E. coli_ is likely important during long-term ROS exposure [42], e.g., when cells transition from early exponential phase to late exponential and stationary phase, which is accompanied by increased ROS production [66]. _E. coli_ YchF is also a substrate of the AAA-protease Lon [67], which is required for cellular homeostasis and for stress-induced developmental changes [68]. Thus, Lon-dependent proteolysis of YchF during stress conditions could additionally contribute to the decline of the YchF levels. _E. coli_ YchF co-purifies with catalases and many antioxidant proteins, including thioredoxin or glutaredoxin, suggesting that YchF could act as a direct inhibitor of antioxidant enzymes [20; 26]. This is supported by a reduction in catalase activity when YchF is over-produced [20]. However, YchF does not inhibit the catalase activity of KatG in vitro [42], indicating that the reduced catalase activity is likely an indirect effect. On the other hand, the interaction of YchF with thioredoxin was shown to be required for dissociating the YchF dimer, which is formed by ROS-induced oxidation of the conserved Cys35-residue and intermolecular disulphide-bridge formation [26]. Within the YchF dimer, the ATP binding site is covered and hence dimerization prevents ATP hydrolysis [26].