# Cellular Self-Digestion and Persistence in Bacteria
## 3 What Are the Global Regulators of the Cellular Self-Digestion Network?  
Self-digestion is initiated at the beginning of the starvation response, when bacteria begin to degrade their cytoplasmic membrane, cell wall, proteins, RNA, and DNA [67; 105; 106; 107; 108]. This process is mediated by a large number of degradative enzymes found in the bacterial cytoplasm, membrane, and periplasm [109]. Critically, despite their prevalence, the regulatory mechanisms that control expression of these molecules at the transcriptional level are largely unknown. Upon nutrient depletion or when cells enter stationary phase, significant changes in the intracellular levels of many global regulators, including DksA, Rpos, and ppGpp, are observed [90; 110; 111; 112; 113; 114; 115; 116; 117]. However, these regulators have many functions beyond just protecting the cell during starvation. Consequently, they are also induced in response to various stresses, such as oxidative stress, heat/cold shock, osmotic pressure, low pH, ultraviolet (UV)-induced DNA damage, high cell density, and toxic chemicals [118; 119; 120; 121; 122; 123; 124; 125].  
One such regulator is the stationary-phase transcription factor \(\sigma^{\rm S}\) (i.e., the alternative sigma factor). Expression of this protein, which is encoded by the _rpoS_ gene, dramatically increases in stationary phase, where it functions to regulate the expression of numerous stress-related genes [90; 112; 113; 114; 115; 116; 117]. Strains lacking \(\sigma^{\rm S}\) show rapid cessation of growth upon introduction to starvation conditions in _E. coli_[127]. Notably, although the formation of bacterial persister cells in response to polyamines has been attributed to overexpression of _rpoS_[128], the effect of _rpoS_ deletion on persistence depends on the experimental conditions and strains being used [129; 130; 131]. However, RpoS is not the only sigma factor in bacteria; other well-studied sigma factors include \(\sigma^{\rm B}\), \(\sigma^{\rm C}\), \(\sigma^{\rm D}\), and \(\sigma^{\rm H}\) in _Bacillus subtilis_[132; 133; 134; 135], \(\sigma^{\rm E}\), \(\sigma^{\rm H}\), and \(\sigma^{\rm S}\) in _Pseudomonas aeruginosa_[136; 137], and \(\sigma^{\rm B}\), \(\sigma^{\rm H}\), and \(\sigma^{\rm M}\) in _Corynebacterium glutamicum_[138]. In _E. coli_, sigma factors \(\sigma^{\rm H}\) and \(\sigma^{\rm N}\) are overexpressed during stationary phase and can help cells survive during starvation [139; 140]. Similarly, the absence of \(\sigma^{\rm E}\) drastically compromises viability of _Salmonella_ cells in stationary phase [141].  
In addition to sigma factors, the transcription factor DksA and the alarmone molecule (p)ppGpp, which is synthesized by the RelA and SpoT enzymes, form a global regulator of the stringent response that is activated upon carbon source depletion or amino acid starvation [142; 143; 144]. Induction of the stringent response has been shown to induce persister formation in bacteria [10; 45; 145], and numerous research groups have reported reduced persister levels in \(\Delta relA\), \(\Delta spoT\), and \(\Delta dksA\) strains [11; 18; 146; 147; 148; 149]. However, although molecules such as RpoS, DksA, and ppGpp have been extensively studied in the field of persister research [146; 147; 148; 149; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149], the question of whether they directly regulate persister mechanisms associated with self-digestion has yet to be answered. It is also possible that degradative enzymes may be constitutively expressed, which results in the accumulation of the enzymes in stationary-phase cells; however, this hypothesis needs to be verified.