## 5 General Stress Pathways Activated in Response to PPCs  
Major molecular chaperone and protease systems that accomplish essential functions to control protein quality under stress conditions are induced by _Lactobacillus_ in the presence of PPCs (Figure 2). The DnaK system (DnaK chaperone, co-chaperone DnaJ, and nucleotide exchange factor GrpE) is one of the chaperones involved in the molecular responses to PPCs. In _L. plantarum_ WCFS1, components of the DnaK system were induced in the presence of \(p\)-CA or RSV (Figure 2). Another chaperone responsive to PPCs is the refolding GroES/GroEL system. GroES was transcriptionally induced in \(L\). _plantarum_ WCFS1 by \(p\)-CA, RSV, OLE, and HXT, while _groEL_ was induced by these PPCs except by \(p\)-CA (Figure 2). Proteomic studies have shown that GroES is also notably induced at high tannic acid concentrations in \(L\). _plantarum_[43], while GroEL is induced in response to tannic acid in _Lentilactobacillus_ _hilgardii_[44] or the flavonoid glycoside rutin in _Lactobacillus_ NCFM [45]. Several members of the Clp ATP family of proteases were induced by PPCs in _Lactobacillus_. Transcriptomic and proteomic studies have shown that the ClpP protease is induced by \(p\)-CA in \(L\). _plantarum_ WCFS1 [25], _Lacticaseibacillus casei_ BL23 [24], and by rutin in \(L\). _acidophilus_ NCFM. The ClpC and ClpE proteases, which can associate with the ClpP protease in proteolytic complexes, are induced by \(p\)-CA in \(L\). _plantarum_ WCFS1 (Figure 2), whereas ClpE is induced by rutin in \(L\). _acidophilus_ NCFM. The expression of _clpE_, but not of _clpP_, was induced by RSV in \(L\). _plantarum_ WCFS1 [27] indicating that ClpE acts here as molecular chaperone [46]. In addition, \(L\). _acidophilus_ NCFM induced the two-component proteasome (HslV protease/HslU ATPase) in presence of rutin [45]. Other stress-related genes, including heat (_lsp_) and alkaline (_asp_) shock protein-encoding genes, also contribute to phenolic compound resistance in _Lactobacillus__Levilactobacillus__brevis_ cells exposed to ferulic acid (a hydroxycinnamic acid) [23] induced an _lsp_ gene highly similar to the _lsp_ genes induced by \(p\)-CA in \(L\). _plantarum_. \(L\). _acidophilus_ NCFM also induced an hsp protein (GrpE) in the presence of rutin [45]. The _asp1_ and _asp2_ genes are induced in \(L\). _plantarum_ by OLE [28] and HXT [29], and the Asp1 protein is induced by tannic acid in _L. plantarum_[37]. Interestingly the homologous _L. plantarum asp2_ gene of _L. casei (asp23)_ contributes to gentamicin resistance in this microorganism [47]. Transcriptomic studies have revealed that the stringent response (SR), a conserved bacterial response that transcriptionally affects general stress responses [48; 49], was involved in the molecular adaptation of _L. plantarum_ WCFS1 to several PPCs. Several sets of genes owing to SR, including ribosome, nucleotide, and fatty-acid biosynthesis genes, were downregulated in _L. plantarum_ WCFS1 by _p_-CA [25], OLE [28], or HXT [29]. In _L. brevis_, genes encoding proteins responsible for transcription, translation, and key proteins involved in cell division were strongly downregulated in the presence of ferulic acid [23]. Differential expression of _L. plantarum_ genes coding for enzymes directly involved in the metabolism of (p)ppGpp (the alarmone assumed to trigger the SR), including small translational GTPases and (p)ppGpp synthases, were observed in the presence of HXT [29]. The (p)ppGpp metabolism is interconnected with GTP metabolism and regulates the intracellular concentrations of this nucleotide which, in turn, modulate the biosynthesis of the alarmone [49]. Genes related to GTP biosynthetic and GTP-consuming pathways were differentially regulated by _p_-CA [25], OLE [28], and HXT [29], indicating that GTP regulation is involved in the response to these PPCs, and that maintaining GTP levels within a range is essential for viability under different environmental conditions (Kriel et al. 2012).