Abstract
The molecule guanosine tetraphophosphate (ppGpp) is most commonly considered an alarmone produced during acute stress. However, ppGpp is also present at low concentrations during steady-state growth. Whether ppGpp controls the same cellular targets at both low and high concentrations remains an open question and is vital for understanding growth rate regulation. It is widely assumed that basal ppGpp concentrations vary inversely with growth rate, and that the main function of basal ppGpp is to regulate transcription of ribosomal RNA in response to environmental conditions. Unfortunately, studies to confirm this relationship and to define regulatory targets of basal ppGpp are limited by difficulties in quantifying basal ppGpp. In this Perspective we compare reported concentrations of basal ppGpp in E. coli and quantify ppGpp within several strains using a recently developed analytical method. We find that although the inverse correlation between ppGpp and growth rate is robust across strains and analytical methods, absolute ppGpp concentrations do not absolutely determine RNA synthesis rates. In addition, we investigated the consequences of two separate RNA polymerase mutations that each individually reduce (but do not abolish) sensitivity to ppGpp and find that the relationship between ppGpp, growth rate, and RNA content of single-site mutants remains unaffected. Both literature and our new data suggest that environmental conditions may be communicated to RNA polymerase via an additional regulator. We conclude that basal ppGpp is one of potentially several agents controlling ribosome abundance and DNA replication initiation, but that evidence for additional roles in controlling macromolecular synthesis requires further study.
Highlights
How might a bacteria cell measure its own growth rate? In the model bacterium Escherichia coli, the small molecule guanosine tetraphosphate is closely tied to growth rate control
Due to the circumstances of its discovery, ppGpp is more familiar as a stress or starvation signal. ppGpp and guanosine pentaphosphate, collectively called (p)ppGpp, were first identified in E. coli as compounds produced in strains that inhibit stable RNA synthesis upon amino acid starvation, a phenomenon known as the stringent response (Cashel and Gallant, 1969)
While it might be expected that the cultures expressing ppGpp-insensitive RNA polymerase (RNAP) contain a higher RNA abundance than wild-type, we found that for every medium aside from MOPS/acetate, both mutant strains exhibit equivalent or even less RNA per OD unit than does the wildtype (Figure 2F)
Summary
How might a bacteria cell measure its own growth rate? In the model bacterium Escherichia coli, the small molecule guanosine tetraphosphate (ppGpp) is closely tied to growth rate control. Just as ppGpp strongly inhibits stable RNA synthesis at high concentrations, basal ppGpp mildly inhibits transcriptional initiation from ribosomal RNA (rRNA) promoters, at least partly determining ribosome abundance during steady-state growth (Ryals et al, 1982). Each study observed no significant difference in ppGpp concentrations and growth rates in relA+ and relA−, indicating that SpoT alone is able to establish an inverse correlation between ppGpp and growth rate (Figure 1A).
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