Fig. 1.

Schematic of the ppGpp ribosome dimerization persister (PRDP) model. Stress such as nutrient limitation, osmotic stress, and acid stress induces the stringent response which results in ppGpp formation by RelA/SpoT and generation of cAMP (e.g., upon glucose depletion via the phosphorylated glucose phosphotransfer enzyme, EIIA-P) in E. coli. ppGpp induces hpf, and both ppGpp and cAMP together induce raiA and rmf. RaiA inactivates 70S ribosomes, RMF converts 70S ribosomes into inactive 90S ribosomes, and Hpf converts inactive 90S ribosomes into inactive 100S ribosomes. Moreover, ppGpp binds HflX to likely inactivate it, and cAMP represses hflX. Upon addition of nutrients and removal of the stress, cAMP decreases (due to unphosphorylated EIIA) which stimulates HflX production; HflX dissociates inactive 100S ribosomes into active 70S ribosomes and growth resumes. Since persister cells form in the absence of ppGpp (although at much reduced levels), cAMP by itself and perhaps other mechanisms activate RMF and Hpf as well.