"Just how hungry am I? And what should I do about it?" How bacteria decide.

Escherichia coli bacteria may lack rumbling stomachs, but they know they're hungry when their ribosomes are empty. In starvation conditions, the lack of available amino acids leads to an increase in the cellular concentration of tRNAs that are uncharged with amino acids. The presence of uncharged tRNAs on the ribosome is sensed by the protein RelA in E. coli and other gamma- and beta-proteobacteria, and by close homologs called Rel or RSH in other bacteria. In such starved conditions, RelA-like proteins (from here-on I'll call them RSHs (RelA/SpoT Homologs) produce the small 'alarmone' molecule ppGpp. This onsets the so-called stringent response, where ppGpp induces changes in cell physiology, down-regulating the translation machinery and up-regulating amino acid biosynthesis machinery. It's also involved in responses to other environmental inputs such as glucose and fatty acid and iron availability. Here's a link to great review of ppGpp synthesis, hydrolysis and effects.

It's becoming clear that there is tight and complex regulation by ppGpp, and there are a couple of recent papers to this effect, which I'll briefly discuss. Using microarrays, Traxler et al. have carried out transcriptional profiling of the stringent response in E. coli, the organism where most research on bacterial stress and starvation has been carried out. They studied how ppGpp effects two transcriptional regulons, Lrp (leucine responsive protein that regulates amino acid biosynthesis and transport) and the σ-factor RpoS that regulates general stress response. They found that the Lrp regulon requires only a low level of ppGpp for its induction, while the RpoS regulon is induced only in high concentrations of ppGpp (also see comment by Carlos Balsalobre). Thus, the RpoS-dependent response is only triggered as a kind of emergency measure if the induction of the Lrp-dependent response has been induced and failed to save bacterial population growth.

It is also becoming evident that the production of ppGpp and its effects differ among different bacteria.  The bacterium Caulobacter crescentus lives in environments where amino acid concentrations are generally low. Boutte and Crosson have found that in this organism, ppGpp is synthesised in response to glucose and ammonium starvation, but not amino acid starvation. They find the RSH of this bacterium binds the ribosome, and exhibits "AND-type signaling logic", in which detection of an uncharged tRNA on the ribosome is a necessary but alone, insufficient signal for activation of ppGpp synthesis. This hints at synergistic control, where multiple starvation signals contribute to the accumulation of ppGpp at a high levels. This is different to the "OR-type" logic of E. coli, suggesting the environmental niche of the bug affects how starvation is perceived and dealt with.

The circuitry for ppGpp synthesis and its downstream effects are clearly intricate, involving feedback loops and inter-molecular cross-talk. I'm writing up some bioinformatic work now on the distribution and evolution of RSHs that synthesise or hydrolyse ppGpp, or do both. My results, like those of Boute and Crosson suggest the circuitry is dynamic across bacterial taxa, being often rewired during evolution with the help of gene duplications, domain gain and loss and horizontal gene transfer. This will be blogged of course!

For more posts about the stringent response, check out Vasya's blog

Refs

Traxler MF, Zacharia VM, Marquardt S, Summers SM, Nguyen HT, Stark SE, & Conway T (2011). Discretely calibrated regulatory loops controlled by ppGpp partition gene induction across the 'feast to famine' gradient in Escherichia coli. Molecular microbiology, 79 (4), 830-45 PMID: 21299642

Balsalobre C (2011). Concentration matters!! ppGpp, from a whispering to a strident alarmone. Molecular microbiology, 79 (4), 827-9 PMID: 21299641

Boutte CC, & Crosson S (2011). The complex logic of stringent response regulation in Caulobacter crescentus: starvation signaling in an oligotrophic environment. Molecular microbiology PMID: 21338423